The difficulties of polytherapy: examples from antimicrobial chemotherapy

Medical therapy in patients with more than one pathology means using more pharmaceuticals, which results in a higher risk of drug interactions which are modifications in the action of one drug when it is administered in the presence of another. The consequences can be diminished therapeutic effect or increased adverse reactions. The pharmacological interactions can be either physico-chemical, pharmacokinetic or pharmacodynamic, on the basis of their mechanisms. Pharmacokinetic interactions are the most important and can emerge during various phases of absorption, distribution, metabolism and drug elimination. The absorption of many antimicrobial agents can be modified through various mechanisms. Some drugs (for example the anticholinergics and opiates) or food can slow gastric motility, slowing the absorption and reducing maximum concentrations of the antibiotic. Variations in gastric pH can alter the solubility or chemical stability of molecules such as the beta-lactams, the natural macrolides and some azoles. The bioavailability of these drugs can be reduced due to molecules used to raise gastric pH. Antibiotics such as tetracycline or the fluoroquinolones have reduced bioavailability due to chelation from bi- and trivalent cations. The primary number of clinically relevant pharmacological interactions is correlated with modifications of biotransformation of drugs due to Cytochrome P450 (CYP) hepatic enzymes which are involved in oxidative drug processes, including lipophilic antimicrobial drugs such as the macrolides, the fluoroquinolones (to be considered amphoteric) and the antifungal azole derivatives. CYP3A is probably one of the most important isoenzymes since it contributes to at least the partial transformation of 60% of drugs that undergo oxidation: erythromycin and clarithromycin are CYP3A4 substrates. Many isoenzymes can also be inhibited by antimicrobial drugs, including both antibacterials and antifungals (for example the macrolides, fluoroquinolones, metronidazole, sulfonamides and azole derivatives) with a consequent reduction in the metabolism of other drugs, thus increasing their blood concentrations and possible correlated adverse reactions. On the other hand, rifampicin, rifabutin and some anticonvulsants can induce enzymatic metabolism, causing reduced blood concentrations and lower AUC of itraconazole and voriconazole with possibly lower therapeutic efficacy. This brief review of pharmacological interactions among certain chemotherapeutic agents leads us to believe that this problem is destined to occur with more frequency in daily clinical practice. What is needed is basic knowledge of drug interactions on the part of all physicians who work in the fields of clinical therapeutics with the goal of reducing the high number of medical errors.