TITLE: Probenecid Dosing When Given with Cefazolin: Guidelines and Clinical Effectiveness

Transcription

1 TITLE: Probenecid Dosing When Given with Cefazolin: Guidelines and Clinical Effectiveness DATE: 21 November 2008 RESEARCH QUESTIONS: 1. What is the evidence for the clinical effectiveness of the 1g dose of probenecid when given to prolong the half life of intravenous cefazolin compared to the 2g dose in outpatients with infection? 2. What are the guidelines for dosing of probenecid when given to prolong the half life of intravenous cefazolin in outpatients with infection? METHODS: A limited literature search was conducted on key health technology assessment resources, including PubMed, the Cochrane Library (Issue 4, 2008), University of York Centre for Reviews and Dissemination (CRD) databases, ECRI, EuroScan, international health technology agencies, and a focused Internet search. Results include articles published between 1996 and January 2009, and are limited to English language publications only. No filters were applied to limit the retrieval by study type. Internet links are provided, where available. The summary of findings was prepared from the abstracts of the relevant information. Please note that data contained in abstracts may not always be an accurate reflection of the data contained within the full article. RESULTS: HTIS reports are organized so that the higher quality evidence is presented first. Therefore, health technology assessment reports, systematic reviews, and meta-analyses are presented Disclaimer: The Health Technology Inquiry Service (HTIS) is an information service for those involved in planning and providing health care in Canada. HTIS responses are based on a limited literature search and are not comprehensive, systematic reviews. The intent is to provide a list of sources of the best evidence on the topic that CADTH could identify using all reasonable efforts within the time allowed. HTIS responses should be considered along with other types of information and health care considerations. The information included in this response is not intended to replace professional medical advice, nor should it be construed as a recommendation for or against the use of a particular health technology. Readers are also cautioned that a lack of good quality evidence does not necessarily mean a lack of effectiveness particularly in the case of new and emerging health technologies, for which little information can be found, but which may in future prove to be effective. While CADTH has taken care in the preparation of the report to ensure that its contents are accurate, complete and up to date, CADTH does not make any guarantee to that effect. CADTH is not liable for any loss or damages resulting from use of the information in the report. Copyright: This report contains CADTH copyright material and may contain material in which a third party owns copyright. This report may be used for the purposes of research or private study only. It may not be copied, posted on a web site, redistributed by or stored on an electronic system without the prior written permission of CADTH or applicable copyright owner. Links: This report may contain links to other information on available on the websites of third parties on the Internet. CADTH does not have control over the content of such sites. Use of third party sites is governed by the owners own terms and conditions.

2 first. These are followed by randomized controlled trials (RCTs), controlled clinical trials, observational studies, and evidence-based guidelines. One systematic review, two RCTs, and one observational study were identified pertaining to the clinical effectiveness of probenecid when given to prolong the half life of intravenous cefazolin. No health technology assessments, controlled clinical trials, observational studies, or evidencebased guidelines were identified. OVERALL SUMMARY OF FINDINGS: One systematic review was identified that reviewed the pharmacokinetic and clinical evidence for the use of cefazolin and probenecid for the treatment of skin and soft tissue infections. 1 Studies were included in the review if they evaluated pharmacokinetic and clinical outcomes such as the effect of probenecid on the pharmacokinetics of cefazolin, efficacy, and safety end points. Three pharmacokinetic studies were identified and each found that the addition of probenecid to cefazolin therapy increased the serum concentrations and prolonged the half-life of cefazolin. Two randomized controlled trials were included in the systematic review and were also identified in our literature search. 2,3 Both trials used a probenecid dose of 1g per day and found that the combination of cefazolin and probenecid to be an effective treatment option for skin and soft tissue infections. Authors concluded that there is limited pharmacokinetic and clinical data, but that the limited evidence suggests that daily intravenous cefazolin (2g) and oral probenecid (1g) is effective in treating skin and soft tissue infections. The first trial identified was a randomized double-blind equivalence trial of home-based therapy for cellulitis. 2 Patients were randomized to either intravenous cefazolin (2g) plus oral probenecid (1g) or to intravenous ceftriaxone (1g) plus oral placebo. For the cefazolin/probecenid group, (n=59), clinical cure was obtained in 86% of patients and 96% of patients in the ceftriaxone/placebo group (n=57). The median antibiotic concentrations were 2.35 µg/ml for cefazolin and µg/ml for ceftriaxone. Adverse reaction rates were similar in each arm. Authors concluded that the once daily regiment of cefazolin and probenecid was a practical and effective treatment option for cellulitis. In the other included RCT, 194 patients presenting to the emergency department with a diagnosis of cellulitis or soft tissue infection were randomized to receive cefazolin (2g) and probenecid (1g) or ceftriaxone (2g) and probenecid (1g). 3 There was no statistically significant difference between the ceftriaxone group (n=96) and the cefazolin group (n=98) group with regard to cause of infection, site of infection, duration of treatment, noncompliance, or the need for incision or drainage of the wound. Authors found that cefazolin and ceftriaxone in combination with 1g of probenecid are equally efficacious in the outpatient treatment of skin and soft tissue infections. They indicated the potential for cost savings of using cefazolin therapy over ceftriaxone for the treatment of such infections. The only study to assess the effectiveness of probenecid at a dose of 2g/day (500g four times daily) was a prospective non-randomized unblinded study. 4 A total of 26 patients received either 2g cefazolin every 8 hours, or 2g cefazolin once daily plus probenecid (500g four times daily). For patients given cefazolin once daily with probenecid, peak serum concentrations were mg/L on day one and mg/L on day five. In patients that received cefazolin every eight hours, day one peak serum concentrations were mg/l and day five concentrations were mg/l. Authors concluded that when given at a dose of 500g four times daily, probenecid was effective in maintaining therapeutic serum concentrations of cefazolin. Probenecid Dosing When Given with Cefazolin 2

3 Overall, probenecid seems to be effective in maintaining therapeutic serum concentrations of cefazolin for the treatment of infection. 1-4 The two RCTs used a probenecid dose of 1g, whereas the observational study used a 2g dose of probenecid. No studies were identified that compared probenecid at doses of 1g/day versus 2g/day. It is therefore unclear as to whether there are differences in the effectiveness of probenecid at those doses. No guidelines were identified for the dosing of probenecid. Probenecid Dosing When Given with Cefazolin 3

4 REFERENCES SUMMARIZED: Health technology assessments Systematic reviews and meta-analyses 1. Cox VC, Zed PJ. Once-daily cefazolin and probenecid for skin and soft tissue infections. Ann Pharmacother 2004;38(3): PubMed: PM Randomized controlled trials 2. Grayson ML, McDonald M, Gibson K, Athan E, Munckhof WJ, Paull P, et al. Once-daily intravenous cefazolin plus oral probenecid is equivalent to once-daily intravenous ceftriaxone plus oral placebo for the treatment of moderate-to-severe cellulitis in adults. Clin Infect Dis 2002;34(11): PubMed: PM Brown G, Chamberlain R, Goulding J, Clarke A. Ceftriaxone versus cefazolin with probenecid for severe skin and soft tissue infections. J Emerg Med 1996;14(5): PubMed: PM Controlled clinical trials Observational studies 4. Spina SP, Dillon EC, Jr. Effect of chronic probenecid therapy on cefazolin serum concentrations. Ann Pharmacother 2003;37(5): PubMed: PM Guidelines and recommendations PREPARED BY: Kristen Moulton, B.A., Research Assistant Jessie Cunningham, M.I.St., Information Specialist Health Technology Inquiry Service htis@cadth.ca Tel: Probenecid Dosing When Given with Cefazolin 4

5 APPENDIX FURTHER INFORMATION: Observational studies 5. Khangura S, Wallace J, Kissoon N, Kodeeswaran T. Management of cellulitis in a pediatric emergency department. Pediatr Emerg Care 2007;23(11): PubMed: PM Lun E, Robertson P, Fryters S, Friesen E, Blondel-Hill E. Effect of Probenecid on Cefazolin: a Double Blind, Randomized, Pharmacokinetic and Tolerance Study. Abstr Intersci Conf Antimicrob Agents Chemother Intersci Conf Antimicrob Agents Chemother Sep 26-29; 39(1) (abstract no. 5). Edmonton (AB): Interscience Conference on Antimicrobial Agents and Chemotherapy;1999. Available: (accessed 2008 Nov 12). Product information 7. Lexi-Comp, Inc. Cefazolin: drug information. [online database]. Waltham (MD): Uptodate; 2008 (accessed 2008 Nov 12). (See Drug interactions) 8. Probenecid: CPhA monograph. In: e-theraputics+. [online database]. Ottawa (ON): Canadian Pharmacists Association; 2008 (accessed 2008 Nov 12). (See Table 2) 9. Lexi-Comp, Inc. Probenecid: drug information. [online database]. Waltham (MA): Uptodate; 2008 (accessed 2008 Nov 12). (See Dosing information) 10. Cefazolin: VIHA (south island) IV monograph. Victoria (BC): Vancouver Island Health Authority; Available: B4BB-67C75F66FC62/9563/cefazolin1.pdf (accessed 2008 Nov 12). Probenecid Dosing When Given with Cefazolin 5