Infectious Diseases in Clinical Practice:
Snapshots for September 2006
Pasquale, Timothy R. PharmD
NITAZOXANIDE FOR THE TREATMENT OF CLOSTRIDIUM DIFFICILE COLITIS
Musher et al1 reported the results of a prospective, randomized, double-blind study comparing nitazoxanide with metronidazole in treating hospitalized patients with Clostridium difficile colitis. The study was conducted at 7 medical centers in the United States and included patients older than 18 years with diarrhea (defined as ≥3 unformed stools within in a 24-hour period), an enzyme immunoassay result positive for C. difficile toxin, and 1 or more of the following findings: fever, abdominal pain, or leukocytosis. The patients were randomized to 1 of 3 treatment groups including (1) metronidazole 250 mg orally every 6 hours for 10 days, (2) nitazoxanide 500 mg orally every 12 hours for 7 days, and (3) nitazoxanide 500 mg orally every 12 hours for 10 days. The primary analysis included 34 patients in the metronidazole group, 40 patients in the 7-day-therapy nitazoxanide group and 36 patients in the 10-day-therapy nitazoxanide group. The primary end point of the study was clinical response after 7 days of treatment and defined as the return to healthy bowel habits and no other clinical findings attributable to C. difficile infection. The demographic data were similar between the treatment groups. Clinical response occurred in 28 (82.4%) of the 34 patients who received metronidazole compared with 36 (90.0%) of the 40 patients in the 7-day-therapy nitazoxanide group and 32 (88.9%) of the 36 patients in the 10-day-therapy nitazoxanide group (difference, 7.1%; 95% confidence interval, −7.1% to 25.5%). Sustained response, 31 days after beginning treatment, was reported in 19 (57.6%) of the 33 patients who received metronidazole compared with 25 (65.8%) of the 38 patients randomized to the 7-day-therapy nitazoxanide group and 26 (74.3%) of the 35 patients randomized to the 10-day-therapy nitazoxanide group (P = 0.34). The overall 31-day mortality rate in the study was 9.1%.
During the past 20 years, specific therapy against C. difficile colitis has been limited to oral vancomycin and metronidazole. These 2 agents have been effective agents, and there has been considerable debate as to which is the preferred agent. Several authorities recommend metronidazole first line based on issues such as cost, therapeutic equivalence to vancomycin, and less concern with promoting vancomycin-resistant enterococcus. Others prefer vancomycin because of its pharmacological properties including its good in vitro activity against C. difficile, high colonic concentrations, and not absorbed orally. The prevalence and severity of C. difficile colitis has increased recently. In addition, there have been reports with C. difficile colitis more refractory to standard therapy leading to a conclusion that new therapies are needed. Musher et al1 reports on the first published study evaluating nitazoxanide for the treatment of C. difficile colitis in humans. Nitazoxanide pharmacologically appears to be an "ideal" drug for the treatment of C. difficile colitis because it has good in vitro activity against C. difficile and high colonic concentration after oral administration. Nitazoxanide was compared with metronidazole and nitazoxanide was found to be at least as effective as metronidazole in treating C. difficile colitis. In addition, there was a trend (not statistically significant) toward better sustained response 31 days after beginning treatment in patients that received nitazoxanide for either 7 or 10 days compared with those that received metronidazole for 10 days. One limitation of the study was the small sample size. The results of this study are encouraging and provide clinicians with data that nitazoxanide may be an alternative agent in patients who are not responding to current standard of therapy. In addition, it provides evidence for further investigation of the effectiveness of nitazoxanide in a larger clinical trial ideally comparing it with vancomycin in patients with C. difficile colitis.
LINEZOLID AND SEROTONERGIC DRUG INTERACTIONS: A RETROSPECTIVE SURVEY
Taylor et al2 reported on a retrospective chart review to determine the frequency, significance, and risk factors for serotonergic drug interactions between linezolid and selective serotonin reuptake inhibitors (SSRIs) or venlafaxine. The patients included in the chart review were inpatients at Mayo Clinic (Rochester, MN) with concomitant orders or therapy within 14 days for linezolid and an SSRI or venlafaxine during the same hospitalization during April 2000 to November 2004. A total of 72 patients were included in the study, of which 52 patients received concomitant therapy with linezolid and an SSRI or venlafaxine, and 20 patients received linezolid and SSRI within 14 days. The authors used Sternbach criteria and Boyer algorithm to help identify clinical features of serotonin syndrome. Sixty-eight patients were ruled out for a diagnosis of serotonin syndrome. Two patients who did not receive concomitant therapy but did receive fluoxetine within 14 days of linezolid were classified as having low probability of serotonin syndrome. In each of these patients, therapy was continued, and the signs and symptoms of serotonin syndrome did not progress. Two patients who received concomitant therapy were considered to have high probability of serotonin syndrome. In one case, linezolid therapy was discontinued, and in the other case, SSRI was discontinued. The signs and symptoms of serotonin syndrome resolved within 24 to 48 hours after discontinuation of concomitant therapy.
Linezolid is a relatively weak, reversible, nonselective monoamine oxidase inhibitor. This property has a potential clinical implication when linezolid is concomitantly administered with adrenergic and serotonergic agents. Several case reports of serotonin syndrome associated with the concomitant therapy with linezolid and SSRIs have been published.2 The package insert for linezolid contains a precaution regarding the potential interaction between linezolid and other serotonergic agents.3 Linezolid is an appealing agent for clinical use for several reasons including in vitro spectrum, availability both orally and intravenous, and increasing number of reports and clinical trials demonstrating its effectiveness in a variety of clinical indications. The frequency of linezolid prescribing can be expected to increase, and the clinical implication of the interaction between linezolid and serotonergic agents comes to the forefront for the clinicians. Serotonin syndrome can have significant morbidity and mortality effects and is by no means a predictable adverse drug reaction. In the retrospective review by Taylor et al,2 72 patients were either concomitantly on linezolid and SSRI or venlafaxine or received them within a 14-day period. Of the 72 patients, only 2 patients (3%) were found to have a high probability of serotonin syndrome by their criteria used. Symptoms of serotonin syndrome resolved upon discontinuation of serotonergic therapy. There are several limitations to this report including its retrospective nature and the fact that only documented signs and symptoms of serotonin syndrome could be assessed. If a situation arises where a physician was unaware of the signs and symptoms of serotonin syndrome, these clinical features may not have been documented in the patient's chart. In considering these limitations, this review does provide clinicians with some data or assurance that if clinically indicated, patients may be prescribed linezolid while concomitantly on a serotonergic agent and be safely monitored for serotonin syndrome. If serotonin syndrome is suspected, serotonergic agents should be promptly discontinued.
A RANDOMIZED, OPEN-LABEL, MULTICENTER COMPARATIVE STUDY OF THE EFFICACY AND SAFETY OF PIPERACILLIN-TAZOBACTAM AND CEFEPIME FOR THE EMPIRICAL TREATMENT OF FEBRILE NEUTROPENIC EPISODES IN PATIENTS WITH HEMATOLOGIC MALIGNANCIES
Bow et al4 reported the results of a multicenter, randomized, open-label clinical trial evaluating the efficacy and safety of piperacillin-tazobactam compared with cefepime in patients undergoing treatment of leukemia or hematopoietic stem cell transplantation who were hospitalized for empirical treatment of febrile neutropenic episodes. Patients were enrolled from 34 university-affiliated tertiary care medical centers in the United States, Canada, and Australia. A total of 265 patients were randomized to receive piperacillin-tazobactam 4.5 g IV every 6 hours, and 263 patients were randomized to receive cefepime 2 g IV every 8 hours. The primary outcome was treatment success without regimen modification assessed at 72 hours of therapy, end of therapy, and test of cure review in the modified intent-to-treat population (patients receiving at least 1 dose of the study agents). The primary objective of the study was to demonstrate piperacillin-tazobactam to be noninferior to cefepime in the modified intent-to-treat analysis. The success rates for piperacillin-tazobactam and cefepime were 57.7% (153/265) and 48.3% (127/263), respectively, at 72 hours of therapy (P = 0.04); 39.6% (105/265) and 31.6% (83/263), respectively, at the end of treatment (P = 0.06); and 26.8% (71/263) and 20.5% (54/263), respectively, at the test of cure visit (P = 0.11). Piperacillin-tazobactam was noninferior to cefepime at all time points (P ≤ 0.0001). The study agents were well tolerated. Multivariate analysis revealed piperacillin-tazobactam to be independently associated with treatment success (odds ratio, 1.65; 95% confidence intervals, 1.04-2.64; P = 0.035).
The primary objective of the study by Bow et al4 was to show noninferiority of piperacillin-tazobactam compared with cefepime in the modified intent-to-treat analysis, and that was accomplished. An interesting finding was multivariate analysis revealing randomization to piperacillin-tazobactam to be an independent predictor of treatment success and defervescence. This finding goes along with a recent meta-analysis that revealed monotherapy with cefepime for febrile neutropenia to be associated with increased mortality compared with imipenem/cilastatin, meropenem, piperacillin-tazobactam, and ceftazidime.5 Treatment failures occurred less frequently in patients receiving piperacillin-tazobactam (137/265; 51.7%) than those receiving cefepime (134/263; 61.2%) (odds ratio, 0.68; 95% confidence interval, 0.48-0.96; P = 0.027). Limitations of the study include the lack of double-blinding, and early modification of the primary empirical antibiotic regimen with the addition of a glycopeptide was at the discretion of the investigator. It is important to note that treatment failure was defined as death due to infection or the administration of any additional antibacterial agent for persistent fever, lack of improvement, progressive infection, or new bacterial infection. Cox proportional hazard models were used to examine factors associated with time to defervescence, and the 2 factors less likely to be associated with earlier defervescence were study enrollment in the United States and glycopeptide antibiotic treatment modification. The authors do make an important note that this may be the result of more patients in the US centers at risk for nonresponse or a case of US physicians being more likely to add a glycopeptide in patients with persistent fever that was perceived to be a nonresponse.
1. Musher DM, Logan N, Hamill RJ, et al. Nitazoxanide for the treatment of Clostridium difficile colitis. Clin Infect Dis. 2006;43:421-427.
2. Taylor JJ, Wilson JW, Estes LL. Linezolid and serotonergic drug interactions: a retrospective survey. Clin Infect Dis. 2006;43:180-187.
4. Bow EJ, Rotstein C, Noskin GA, et al. A randomized, open-label, multicenter comparative study of the efficacy and safety of piperacillin-tazobactam and cefepime for the empirical treatment of febrile neutropenic episodes in patients with hematologic malignancies. Clin Infect Dis. 2006;43:447-459.
5. Paul M, Yahav D, Fraser A, et al. Empirical antibiotic monotherapy for febrile neutropenia: systematic review and meta-analysis of randomized controlled trials. J Antimicrob Chemother. 2006;57:176-189.
© 2006 Lippincott Williams & Wilkins, Inc.