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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/ct2/show/NCT03632642




Registration number
NCT03632642
Ethics application status
Date submitted
22/07/2018
Date registered
15/08/2018
Date last updated
16/11/2022

Titles & IDs
Public title
Penicillin Against Flucloxacillin Treatment Evaluation
Scientific title
Pilot Randomised Controlled Trial of Penicillin Versus Flucloxacillin for Definitive Treatment of Invasive Penicillin Susceptible Staphylococcus Aureus
Secondary ID [1] 0 0
HREC/17/QRBW/620
Universal Trial Number (UTN)
Trial acronym
PANFLUTE
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Staphylococcus Aureus 0 0
Condition category
Condition code
Infection 0 0 0 0
Other infectious diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Benzylpenicillin
Treatment: Drugs - Flucloxacillin

Active Comparator: Benzylpenicillin arm - 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.

Active Comparator: Flucloxacillin arm - 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.


Treatment: Drugs: Benzylpenicillin
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.

Treatment: Drugs: Flucloxacillin
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.
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Feasibility of DOOR
Timepoint [1] 0 0
90 day
Secondary outcome [1] 0 0
Adverse Events
Timepoint [1] 0 0
90 day
Secondary outcome [2] 0 0
Mortality
Timepoint [2] 0 0
14, 42 and 90 days
Secondary outcome [3] 0 0
Time to defervescence
Timepoint [3] 0 0
From randomisation to any period where a temperature is < 37.5 degrees celsius for greater than or equal to 24 hours
Secondary outcome [4] 0 0
Persistent bacteraemia
Timepoint [4] 0 0
Day 3 and day 7
Secondary outcome [5] 0 0
Microbiologic relapse
Timepoint [5] 0 0
Any period within 90 days from randomisation following a negative blood culture at least 3 days prior
Secondary outcome [6] 0 0
Microbiologic treatment failure
Timepoint [6] 0 0
Any period within day 14 to day 90 from randomisation
Secondary outcome [7] 0 0
Healthcare costs
Timepoint [7] 0 0
90 day

Eligibility
Key inclusion criteria
- 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
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
- Patient with a recorded allergy to penicillin including:

1. Hypersensitivity type reaction

2. Stephens-Johnson syndrome

3. Rash

4. 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.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 4
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Withdrawn
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
1/07/2019
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
1/07/2020
Actual
Sample size
Target
Accrual to date
Final
0
Recruitment in Australia
Recruitment state(s)
QLD
Recruitment hospital [1] 0 0
Brisbane Private Hospital - Brisbane
Recruitment postcode(s) [1] 0 0
4000 - Brisbane

Funding & Sponsors
Primary sponsor type
Other
Name
The University of Queensland
Address
Country

Ethics approval
Ethics application status

Summary
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.
Trial website
https://clinicaltrials.gov/ct2/show/NCT03632642
Trial related presentations / publications
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.
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. Erratum In: Circulation. 2015 Oct 27;132(17):e215. Circulation. 2016 Aug 23;134(8):e113. Circulation. 2018 Jul 31;138(5):e78-e79.
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.
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.
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.
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.
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.
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.
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. Erratum In: Clin Infect Dis. 2023 Jan 6;76(1):182.
Public notes

Contacts
Principal investigator
Name 0 0
David Paterson
Address 0 0
UQCCR
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries



Summary Results

For IPD and results data, please see https://clinicaltrials.gov/ct2/show/NCT03632642