Pharmacokinetic aspects of treating infections in the intensive care unit: focus on drug interactions

Pharmacokinetic interactions involving anti-infective drugs may be important in the intensive care unit (ICU). Although some interactions involve absorption or distribution, the most clinically relevant interactions during anti-infective treatment involve the elimination phase. Cytochrome P450 (CYP) 1A2, 2C9, 2C19, 2D6 and 3A4 are the major isoforms responsible for oxidative metabolism of drugs. Macrolides (especially troleandomycin and erythromycin versus CYP3A4), fluoroquinolones (especially enoxacin, ciprofloxacin and norfloxacin versus CYP1A2) and azole antifungals (especially fluconazole versus CYP2C9 and CYP2C19, and ketoconazole and itraconazole versus CYP3A4) are all inhibitors of CYP-mediated metabolism and may therefore be responsible for toxicity of other coadministered drugs by decreasing their clearance. On the other hand, rifampicin is a nonspecific inducer of CYP-mediated metabolism (especially of CYP2C9, CYP2C19 and CYP3A4) and may therefore cause therapeutic failure of other coadministered drugs by increasing their clearance. Drugs frequently used in the ICU that are at risk of clinically relevant pharrmacokinetic interactions with anti-infective agents include some benzodiazepines (especially midazolam and triazolam), immunosuppressive agents (cyclosporin, tacrolimus), antiasthmatic agents (theophylline), opioid analgesics (alfentanil), anticonvulsants (phenytoin, carbamazepine), calcium antagonists (verapamil, nifedipine, felodipine) and anticoagulants (warfarin). Some lipophilic anti-infective agents inhibit (clarithromycin, itraconazole) or induce (rifampicin) the transmembrane transporter P-glycoprotein, which promotes excretion from renal tubular and intestinal cells. This results in a decrease or increase, respectively, in the clearance of P-glycoprotein substrates at the renal level and an increase or decrease, respectively, of their oral bioavailability at the intestinal level. Hydrophilic anti-infective agents are often eliminated unchanged by renal glomerular filtration and tubular secretion, and are therefore involved in competition for excretion. Beta-lactams are known to compete with other drugs for renal tubular secretion mediated by the organic anion transport system, but this is frequently not of major concern, given their wide therapeutic index. However, there is a risk of nephrotoxicity and neurotoxicity with some cephalosporins and carbapenems. Therapeutic failure with these hydrophilic compounds may be due to haemodynamically active coadministered drugs, such as dopamine, dobutamine and furosemide, which increase their renal clearance by means of enhanced cardiac output and/or renal blood flow. Therefore, coadministration of some drugs should be avoided, or at least careful therapeutic drug monitoring should be performed when available. Monitoring may be especially helpful when there is some coexisting pathophysiological condition affecting drug disposition, for example malabsorption or marked instability of the systemic circulation or of renal or hepatic function.