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 (Cipro) 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.

QT prolongation with antimicrobial agents: understanding the significance.

Cardiac toxicity has been relatively uncommon within the antimicrobial class of drugs, but well described for antiarrhythmic agents and certain antihistamines. Macrolides, pentamidine and certain antimalarials were traditionally known to cause QT-interval prolongation, and now azole antifungals, fluoroquinolones and ketolides can be added to the list. Over time, advances in preclinical testing methods for QT-interval prolongation and a better understanding of its sequelae, most notably torsades de pointes (TdP), have occurred. This, combined with the fact that five drugs have been removed from the market over the last several years, in part because of QT-interval prolongation-related toxicity, has elevated the urgency surrounding early detection and characterisation methods for evaluating non-antiarrhythmic drug classes. With technological advances and accumulating literature regarding QT prolongation, it is currently difficult or overwhelming for the practising clinician to interpret these data for purposes of formulary review or for individual patient treatment decisions. Certain patients are susceptible to the effects of QT-prolonging drugs. For example, co-variates such as gender, age, electrolyte derangements, structural heart disease, end organ impairment and, perhaps most important, genetic predisposition, underlie most if not all cases of TdP. Between and within classes of drugs there are important differences that contribute to delayed repolarisation (e.g. intrinsic potency to inhibit certain cardiac ion currents or channels, and pharmacokinetics). To this end, a risk stratification scheme may be useful to rank and compare the potential for cardiotoxicity of each drug. It appears that in most published cases of antimicrobial-associated TdP, multiple risk factors are present. Macrolides in general are associated with a greater potential than other antimicrobials for causing TdP from both a pharmacodynamic and pharmacokinetic perspective. The azole antifungal agents also can be viewed as drugs that must be weighed carefully before use since they also have both pharmacodynamic and pharmacokinetic characteristics that may trigger TdP. The fluoroquinolones appear less likely to be associated with TdP from a pharmacokinetic perspective since they do not rely on cytochrome P450 (CYP) metabolism nor do they inhibit CYP enzyme isoforms, with the exception of grepafloxacin and Ciprofloxacin (Cipro). Nonetheless, patient selection must be carefully made for all of these drugs. For clinicians, certain responsibilities are assumed when prescribing antimicrobial therapy: (i) appropriate use to minimise resistance; and (ii) appropriate patient and drug selection to minimise adverse event potential. Incorporating information learned regarding QT interval-related adverse effects into the drug selection process may serve to minimise collateral iatrogenic toxicity.

Yersinia septic shock following an autologous transfusion in a pediatric patient.

Although the literature on infections transmitted via transfused blood focuses on viruses, Yersinia enterocolitica can also cause severe infections in patients receiving transfusions. A 13-year-old patient developed severe sepsis after an autologous blood transfusion contaminated with Y. enterocolitica. The patient was an otherwise healthy female undergoing posterior spinal fusion for congenital scoliosis. Prior to surgery, the patient donated blood for perioperative and postoperative use. A few days before the donation, she had complained of abdominal pain and was experiencing mild diarrhea. The patient received four units of packed red blood cells (PRBCs) during the surgery. Intraoperatively, the patient developed fever up to 103.6 degrees F, became hypotensive requiring epinephrine and dopamine, and developed metabolic acidosis with serum bicarbonate concentration dropping to 16 mmol/l. The surgery team believed the patient was experiencing malignant hyperthermia and attempted to cool patient during the procedure. Postoperatively, the patient was transferred to the pediatric intensive care unit and treated for severe shock of unknown etiology. The patient further developed disseminated intravascular coagulation. The patient received supportive care and was started on ampicillin/sulbactam on postoperative day (POD) one which was changed to clindamycin, Ciprofloxacin (Cipro) and tobramycin on POD two when blood cultures grew gram-negative bacilli. On POD three, cultures were identified as Y. enterocolitica and antibiotics were changed to tobramycin and cefotaxime based on susceptibility data. Sequelae of the shock included adult respiratory distress syndrome requiring intubation and a tracheostomy and multiple intracranial hemorrhagic infarcts with subsequent seizure disorder. Due to severe lower extremity ischemia, she required a bilateral below the knee amputation. The cultures of the snippets from the bags of blood transfused to the patient also grew Y. enterocolitica. This case illustrates the importance of considering transfusion related bacterial infections in patients receiving PRBCs. All patients in shock following any type of transfusion may require aggressive antibiotic therapy, until the diagnosis and etiology are known. Copyright 2003 Elsevier Science Ltd.

Use of Ciprofloxacin (Cipro) in the treatment of hospitalized patients with intra-abdominal infections.

BACKGROUND: Numerous combination and single-agent antimicrobial regimens are available for the treatment of intra-abdominal infections. Selection of empiric agents must be directed at providing reliable activity against endotoxin-generating Escherichia coli, other gram-negative facultative bacteria, and anaerobes such as Bacteroides fragilis. Safety profiles, pharmacokinetic profiles, and cost-effectiveness must also be considered. Use of fluoroquinolones for the treatment of intra-abdominal infections has recently been advocated. METHODS: We review 2 prospective, comparative clinical trials conducted between 1992 and 2002 that evaluated the efficacy and safety of IV Ciprofloxacin (Cipro) in patients with intra-abdominal infections. Separate pharmacoeconomic analyses conducted for each study are also reviewed. RESULTS: A total of 4 Ciprofloxacin (Cipro) studies (2 clinical, 2 pharmacoeconomic) comprise the database. The combination of Ciprofloxacin (Cipro) plus metronidazole was at least as effective as imipenem/cilastatin and clinically more effective than piperacillin/tazobactam therapy, based on clinical success end points. In 1 trial, treatment success for the clinically valid population was reported for 84% (93/111) of patients treated with IV Ciprofloxacin (Cipro)/metronidazole, 86% (91/106) of those treated with IV/oral Ciprofloxacin (Cipro)/metronidazole, and 81% of those treated with IV imipenem/cilastatin (91/113). The IV/oral Ciprofloxacin (Cipro)/metronidazole regimen had a statistically significant lower mean infection-related cost than the IV only Ciprofloxacin (Cipro)/metronidazole plus imipenem groups (difference of approximately 1100 US dollars; P = 0.029). In the second clinical trial, clinical resolution rates were statistically different for patients receiving IV/oral Ciprofloxacin (Cipro)/metronidazole (74%) versus IV piperacillin/tazobactam therapy (63%; P = 0.047). Ciprofloxacin (Cipro)/metronidazole was more cost-effective compared with piperacillin/tazobactam (2200 US dollars-3600 US dollars lower cost-effective ratios per patient) regardless of whether the patient had a diagnosis of appendicitis or whether a switch to an oral drug was permissible. CONCLUSIONS: In the studies reviewed herein, the combination of Ciprofloxacin (Cipro) plus metronidazole was an effective and safe regimen for the treatment of intra-abdominal infections. This regimen has potential advantages over exclusively IV regimens, including the option of sequential IV/oral therapy, patient convenience, cost savings, and reduced hospital stay.