Penicillin Against Flucloxacillin Treatment Evaluation

Summary

There is theroretical superiority with benzylpenicillin over orther anti-staphylococcal penicillins (ASP) for treatment of penicillin susceptible S. aureus (PSSA) infections due to a lower MIC distribution when compared with ASPs active against PSSA, combined with the ability to obtain higher levels of free non-protein-bound plasma drug concentrations. Although the data to support this theoretical advantage is limited, many clinicians in Australia (and worldwide) use benzylpenicillin for therapy in this situation despite many international guidelines cautioning against this. This uncertainty is significant given that 1) S. aureus bacteraemia (SAB) is associated with a high mortality and significant morbidity, 2) S. aureus is one of the most common organisms isolated from blood cultures, 3) SAB is the most common reason for consultation with an Infectious Disease specialist (which itself has been shown to improve outcomes) and 4) a significant proportion (up to 20%) of SAB isolates in Australia will be reported as susceptible to penicillin, a proportion which appears to be increasing over the past 10 years in Australia and internationally. Given the frequency of PSSA and the associated morbidity and mortality related to SABs in general, a definitive study to determine the optimal therapy for PSSA is required. In a recent survey of Infectious Diseases Physicians and Clinical Microbiologists in Australasia, 87% of respondents were willing to randomise patients to either benzylpenicillin or flucloxacillin for a clinical trial, whist 71% responded that they would switch therapy from flucloxacillin to benzylpenicillin for treatment of PSSA BSIs in clinical practice (unpublished data). Therefore, the investigators see the opportunity to determine the feasibility of a definitive study comparing benzylpenicillin against flucloxacillin (or other ASP) for treatment of PSSA bloodstream infections.

Timeline

Start

2019-07-01

Primary completion

2019-12

Completion

2020-07

Publications

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• Background Baddour LM, Wilson WR, Bayer AS, Fowler VG Jr, Tleyjeh IM, Rybak MJ, Barsic B, Lockhart PB, Gewitz MH, Levison ME, Bolger AF, Steckelberg JM, Baltimore RS, Fink AM, O'Gara P, Taubert KA; American Heart Association Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease of the Council on Cardiovascular Disease in the Young, Council on Clinical Cardiology, Council on Cardiovascular Surgery and Anesthesia, and Stroke Council. Infective Endocarditis in Adults: Diagnosis, Antimicrobial Therapy, and Management of Complications: A Scientific Statement for Healthcare Professionals From the American Heart Association. Circulation. 2015 Oct 13;132(15):1435-86. doi: 10.1161/CIR.0000000000000296. Epub 2015 Sep 15.
• Background Gill VJ, Manning CB, Ingalls CM. Correlation of penicillin minimum inhibitory concentrations and penicillin zone edge appearance with staphylococcal beta-lactamase production. J Clin Microbiol. 1981 Oct;14(4):437-40. doi: 10.1128/jcm.14.4.437-440.1981.
• Background Kaase M, Lenga S, Friedrich S, Szabados F, Sakinc T, Kleine B, Gatermann SG. Comparison of phenotypic methods for penicillinase detection in Staphylococcus aureus. Clin Microbiol Infect. 2008 Jun;14(6):614-6. doi: 10.1111/j.1469-0691.2008.01997.x. Epub 2008 Apr 5.
• Background Coombs GW, Daly DA, Pearson JC, Nimmo GR, Collignon PJ, McLaws ML, Robinson JO, Turnidge JD; Australian Group on Antimicrobial Resistance. Community-onset Staphylococcus aureus Surveillance Programme annual report, 2012. Commun Dis Intell Q Rep. 2014 Mar 31;38(1):E59-69. doi: 10.33321/cdi.2014.38.12.
• Background Nissen JL, Skov R, Knudsen JD, Ostergaard C, Schonheyder HC, Frimodt-Moller N, Benfield T. Effectiveness of penicillin, dicloxacillin and cefuroxime for penicillin-susceptible Staphylococcus aureus bacteraemia: a retrospective, propensity-score-adjusted case-control and cohort analysis. J Antimicrob Chemother. 2013 Aug;68(8):1894-900. doi: 10.1093/jac/dkt108. Epub 2013 Apr 18.
• Background Coombs GW, Daley DA, Thin Lee Y, Pearson JC, Robinson JO, Nimmo GR, Collignon P, Howden BP, Bell JM, Turnidge JD; Australian Group on Antimicrobial Resistance. Australian Group on Antimicrobial Resistance Australian Staphylococcus aureus Sepsis Outcome Programme annual report, 2014. Commun Dis Intell Q Rep. 2016 Jun 30;40(2):E244-54. doi: 10.33321/cdi.2016.40.20.
• Background Cheng MP, Rene P, Cheng AP, Lee TC. Back to the Future: Penicillin-Susceptible Staphylococcus aureus. Am J Med. 2016 Dec;129(12):1331-1333. doi: 10.1016/j.amjmed.2016.01.048. Epub 2016 Feb 26.
• Background Evans SR, Rubin D, Follmann D, Pennello G, Huskins WC, Powers JH, Schoenfeld D, Chuang-Stein C, Cosgrove SE, Fowler VG Jr, Lautenbach E, Chambers HF. Desirability of Outcome Ranking (DOOR) and Response Adjusted for Duration of Antibiotic Risk (RADAR). Clin Infect Dis. 2015 Sep 1;61(5):800-6. doi: 10.1093/cid/civ495. Epub 2015 Jun 25.

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