Penicillin Against Flucloxacillin Treatment Evaluation

NCT03632642 | Withdrawn Phase 4

• 1 other identifier: HREC/17/QRBW/620
• Study Type: interventional
• Target: N/A
• Locations: 1 country
• Sites: 1

Brief 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that they would switch therapy from flucloxacillin to benzylpenicillin for treatment of PSSA BSIs in clinical practice (unpublished data).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.

Conditions

Staphylococcus Aureus

Outcome Measures

Primary Outcomes (1)

• Feasibility of DOOR

  The primary outcome of the study will utilise a desirability of outcome ranking (DOOR) to assess superiority of benzylpenicillin against flucloxacillin.

  90 day

Secondary Outcomes (7)

• Adverse Events

  90 day

• Mortality

  14, 42 and 90 days

• Time to defervescence

  From randomisation to any period where a temperature is < 37.5 degrees celsius for greater than or equal to 24 hours

• Persistent bacteraemia

  Day 3 and day 7

• Microbiologic relapse

  Any period within 90 days from randomisation following a negative blood culture at least 3 days prior

Study Arms (2)

Benzylpenicillin arm

ACTIVE COMPARATOR

Patients randomised to benzylpenicillin will be treated according to Therapeutic Guidelines 15th Edition. During hospitalisation, the standard dose will be 1.8g Q4H IVI for uncomplicated BSIs and 2.4g Q4H for deep-seated or critical illness infections.

Drug: Benzylpenicillin

Flucloxacillin arm

ACTIVE COMPARATOR

Patients randomised to flucloxacillin will be treated according to Therapeutic Guidelines 15th Edition. During hospitalisation, the standard dose will be 2g Q6H IVI or 2g Q4H for deep-seated or criticial illness infections.

Drug: Flucloxacillin

Interventions

Benzylpenicillin DRUG

The study drug will be administered for a minimum of 2 weeks (the minimal currently accepted duration of IV therapy for SAB.) For patients who do not fulfill criteria for 2 weeks of therapy, the duration of treatment will be 4 to 6 weeks and will be made by the treating clinician.

Benzylpenicillin arm

Flucloxacillin DRUG

The study drug will be administered for a minimum of 2 weeks (the minimal currently accepted duration of IV therapy for SAB.) For patients who do not fulfill criteria for 2 weeks of therapy, the duration of treatment will be 4 to 6 weeks and will be made by the treating clinician.

Flucloxacillin arm

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Bloodstream infection with Staphylococcus aureus susceptible to penicillin and negative for penicillinase by phenotypic methods.
• No more than 72 hours has elapsed since the first positive blood culture was drawn
• Patient is aged 18 years and over
• The patient or approved proxy is able to provide informed consent

You may not qualify if:

• Patient with a recorded allergy to penicillin including:
• Hypersensitivity type reaction
• Stephens-Johnson syndrome
• Rash
• Urticaria
• Contraindications based upon other recorded allergies, such as gastrointestinal upset, will be at the discretion of the treating clinician
• Patient with significant polymicrobial bacteraemia (skin contaminants excepted)
• Treated with non-curative intent
• Pregnancy or breast-feeding
• Patient currently receiving concomitant antimicrobials with activity against S. aureus which cannot be ceased or substituted.

Sponsors & Collaborators

• The University of Queensland: lead

Study Sites (1)

Brisbane Private Hospital

Brisbane, Queensland, 4000, Australia

Location

Related Publications (9)

• Kirby WM. EXTRACTION OF A HIGHLY POTENT PENICILLIN INACTIVATOR FROM PENICILLIN RESISTANT STAPHYLOCOCCI. Science. 1944 Jun 2;99(2579):452-3. doi: 10.1126/science.99.2579.452.

  PMID: 17798398 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.

  PMID: 26373316 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.

  PMID: 6974738 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.

  PMID: 18397333 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.

  PMID: 25409357 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.

  PMID: 23599360 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.

  PMID: 27522136 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.

  PMID: 26924388 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.

  PMID: 26113652 BACKGROUND

MeSH Terms

Conditions

Staphylococcal Infections

Interventions

Penicillin G; Floxacillin

Condition Hierarchy (Ancestors)

Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections

Intervention Hierarchy (Ancestors)

Penicillins; beta-Lactams; Lactams; Amides; Organic Chemicals; Sulfur Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Cloxacillin; Oxacillin

Study Officials

• David Paterson

  UQCCR

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: The study will be a pilot open-label multicentre randomised trial that is investigator-initiated comparing two drug regimens: benzylpenicillin vs. flucloxacillin for penicillin susceptible S. aureus bloodstream infections. We will aim to enrol 60 patients (30 in each arm) over a 12-month period. The participation duration for each enrolled patient is 90 days. Data will be collected for the participants from the date of when the first positive blood culture was obtained, which will be within 72 hours of enrollment. Consented patients will be randomised on day 1 (the day of randomisation) to either benzylpenicillin or flucloxacillin.

Study Record Dates

• First Submitted: July 22, 2018
• First Posted: August 15, 2018
• Study Start: July 1, 2019
• Primary Completion: December 1, 2019
• Study Completion: July 1, 2020
• Last Updated: November 16, 2022

Record last verified: 2018-08

Locations

AU (1)