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Not Recruiting

Efficacy and Safety of 7 vs 14 Days of Antibiotic Therapy with Meropenem, Aztreonam, and Levofloxacin in Pseudomonas aeruginosa Bacteremia

Trial ID: 2023-508441-41-00
Protocol: SHORTEN-II
Sponsor: Fundacion Para La Gestion De La Investigacion En Salud De Sevilla

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Diseases & Conditions

Pseudomonas infection

Objectives

The primary objective of this study is to determine if a 7-day antibiotic treatment regimen is superior to a 14-day regimen in the treatment of **Pseudomonas aeruginosa** bacteremia. This evaluation will consider both the effectiveness of the shorter regimen and its potential to reduce serious adverse events and antibiotic exposure. Clinically, this is significant as it may lead to optimized treatment protocols that minimize patient exposure to antibiotics, potentially reducing the risk of adverse effects and antibiotic resistance.

Secondary objectives include:

Determining whether the short regimen is non-inferior to the long regimen in terms of recurrence of infection and mortality, and assessing the safety of antibiotic treatment interruption at the individual level using a simple clinical decision.
Describing the adverse effects and superinfections, particularly those caused by multidrug-resistant bacteria and **Clostridioides difficile** in both treatment regimens.
Analyzing the efficiency of short regimens in terms of the number of treatment days and days of hospital stay avoided at the end of the follow-up period.
Determining risk factors related to treatment failure and risk of recurrence.
Confirming recurrence of infections by sequencing **Pseudomonas aeruginosa** isolates that occur during follow-up.
Comparing the effect of short and long treatment regimens on the preservation of the diversity of the intestinal microbiota.

Participants

The clinical trial focuses on adult patients aged 18 years and older, both **male** and **female**, who are experiencing **bacteremia** due to Pseudomonas aeruginosa. The study population is not considered vulnerable, and participants have already received 6 days (+/-1) of active antibiotic treatment against the bacteremia, counted from the date of extraction of the first positive blood culture until the moment of randomization. The sponsor has not provided information regarding the total number of participants. Participants were selected based on their current health status, specifically the presence of bacteremia due to P. aeruginosa, and their ability to provide informed consent. No specific lifestyle considerations such as diet or physical activity are mentioned as part of the selection criteria.

Plans and Procedures

The clinical trial is designed to evaluate the **efficacy** and safety of a 7-day versus a 14-day antibiotic treatment regimen for bacteremia caused by **Pseudomonas aeruginosa**. This is a multicenter, randomized, double-blind, controlled trial with a DOOR/RADAR analysis. The trial aims to determine if the shorter treatment duration is superior in terms of effectiveness and reduction of serious adverse events and antibiotic exposure. The trial is expected to run from May 20, 2022, to September 30, 2025, with an estimated participant involvement of up to 90 days post-treatment.

Participants will undergo a series of study visits, beginning with an inclusion visit where eligibility is confirmed based on criteria such as age (18 years or older), confirmed bacteremia due to **Pseudomonas aeruginosa**, and having received 6 days (+/-1) of active antibiotic treatment. Informed consent is required for participation. Following randomization, participants will be assigned to either the 7-day or 14-day treatment group. The primary endpoint is the number of days of antibiotic treatment and the DOOR scale category at the end of follow-up, which is 30 days after the completion of appropriate antibiotic treatment.

Secondary endpoints include all-cause mortality, clinical cure, treatment failure, superinfections, serious adverse events, days of hospital stay, and recurrences, assessed at 30 and 90 days post-treatment. Follow-up visits will be conducted to monitor these outcomes. The end-of-study visit will occur at the 90-day mark, concluding the participant's involvement in the trial. Conditions that may lead to early termination from the study include withdrawal of consent, significant protocol deviations, or adverse events that necessitate discontinuation of the study drug.

Treatment

The clinical trial involves the administration of several **experimental medications** and comparator treatments to evaluate the efficacy and safety of a 7-day versus a 14-day antibiotic treatment regimen for bacteremia caused by *Pseudomonas aeruginosa*. The experimental medication, **Meropenem Qilu**, is provided as a 1 g powder for solution for injection/infusion. It is administered intravenously with a maximum daily dose of 6 g and a total dose of 42 g over a 7-day treatment period. The active substance is **meropenem**, a chemical compound, and the pharmaceutical form is a solution for injection/infusion.

**Azactam** is another medication used in the trial, available as a 1 g powder for solution for injection. It is administered intravenously with a maximum daily dose of 8 g and a total dose of 56 g over a 7-day treatment period. The active substance is **aztreonam**, a chemical compound, and the pharmaceutical form is a solution for injection.

**Levofloxacino Normon** is provided as 500 mg film-coated tablets, administered orally. The maximum daily dose is 1 g, with a total dose of 14 g over a 14-day treatment period. The active substance is **levofloxacin hemihydrate**, a chemical compound, and the pharmaceutical form is a film-coated tablet.

**Amicacina Braun** is available as a 500 mg solution for injection, administered intravenously. The maximum daily dose is 3.6 g, with a total dose of 25.2 g over a 7-day treatment period. The active substance is **amikacin**, a chemical compound, and the pharmaceutical form is a solution for injection.

**Colistimetato de sodio Accord** is provided as a powder for solution for injection/infusion, containing 2 million IU of colistimethate sodium. It is administered intravenously with a maximum daily dose of 9 million IU and a total dose of 126 million IU over a 14-day treatment period. The active substance is a mixture, and the pharmaceutical form is a solution for injection/infusion.

**Ciprofloxacino Aurovitas** is available as 750 mg film-coated tablets, administered orally. The maximum daily dose is 1.5 g, with a total dose of 21 g over a 14-day treatment period. The active substance is **ciprofloxacin**, a chemical compound, and the pharmaceutical form is a film-coated tablet.

**Levofloxacino Netpharmalab** is provided as a 5 mg/ml solution for infusion, administered intravenously. The maximum daily dose is 1 g, with a total dose of 14 g over a 14-day treatment period. The active substance is **levofloxacin**, a chemical compound, and the pharmaceutical form is a solution for infusion.

**CIPROFLOXACINO KABI** is available as a 2 mg/ml solution for infusion, administered intravenously. The maximum daily dose is 1.2 g, with a total dose of 16.8 g over a 14-day treatment period. The active substance is **ciprofloxacin**, a chemical compound, and the pharmaceutical form is a solution for infusion.

**Ceftazidima Sala** is provided as a 1,000 mg powder for solution for injection, administered intravenously. The maximum daily dose is 6 g, with a total dose of 84 g over a 14-day treatment period. The active substance is **ceftazidime**, a chemical compound, and the pharmaceutical form is a solution for injection.

**Tobramicina NORMON** is available as a 100 mg/2 ml solution for injection, administered intravenously. The maximum daily dose is 0.84 g, with a total dose of 11.76 g over a 14-day treatment period. The active substance is **tobramycin**, a chemical compound, and the pharmaceutical form is a solution for injection.

**MONOFLOX** is provided as 500 mg film-coated tablets, administered orally. The maximum daily dose is 1 g, with a total dose of 7 g over a 7-day treatment period. The active substance is **levofloxacin hemihydrate**, a chemical compound, and the pharmaceutical form is a film-coated tablet.

**Fetcroja** is available as a 1 g powder for concentrate for solution for infusion, administered intravenously. The maximum daily dose is 3 g, with a total dose of 42 g over a 14-day treatment period. The active substance is **cefiderocol**, a chemical compound, and the pharmaceutical form is a solution for infusion.

**Zavicefta** is provided as a 2 g/0.5 g powder for concentrate for solution for infusion, administered intravenously. The maximum daily dose is 7.5 g, with a total dose of 105 g over a 14-day treatment period. The active substances are **ceftazidime** and **avibactam**, both chemical compounds, and the pharmaceutical form is a solution for infusion.

**Piperacilina/Tazobactam Accord** is available as a 4 g/0.5 g powder for solution for infusion, administered intravenously. The maximum daily dose is 13.5 g, with a total dose of 189 g over a 14-day treatment period. The active substances are **piperacillin** and **tazobactam**, both chemical compounds, and the pharmaceutical form is a solution for infusion.

**Imipenem/Cilastatina Kabi** is provided as a 500/500 mg powder for solution for infusion, administered intravenously. The maximum daily dose is 4 g, with a total dose of 28 g over a 7-day treatment period. The active substances are **cilastatin sodium** and **imipenem monohydrate**, both chemical compounds, and the pharmaceutical form is a solution for infusion.

**Tobramicina NORMON** is available as a 50 mg/2 ml solution for injection, administered intravenously. The maximum daily dose is 0.84 g, with a total dose of 5.88 g over a 7-day treatment period. The active substance is **tobramycin**, a chemical compound, and the pharmaceutical form is a solution for injection.

**MEROPENEM QILU** is provided as a 1 g powder for solution for injection/infusion, administered intravenously. The maximum daily dose is 6 g, with a total dose of 84 g over a 14-day treatment period. The active substance is **meropenem**, a chemical compound, and the pharmaceutical form is a solution for injection/infusion.

**Quofenix** is available as a 300 mg powder for concentrate for solution for infusion, administered intravenously. The maximum daily dose is 0.6 g, with a total dose of 4.2 g over a 7-day treatment period. The active substance is **delafloxacin**, a chemical compound, and the pharmaceutical form is a solution for infusion.

**Colistimetato de sodio Altan Pharma** is provided as a powder for solution for injection/infusion, containing 2 million IU of colistimethate sodium. It is administered intravenously with a maximum daily dose of 9 million IU and a total dose of 63 million IU over a 7-day treatment period. The active substance is a mixture, and the pharmaceutical form is a solution for injection/infusion.

**Vaborem** is available as a 1 g/1 g powder for concentrate for solution for infusion, administered intravenously. The maximum daily dose is 12 g, with a total dose of 168 g over a 14-day treatment period. The active substances are **meropenem** and **vaborbactam**, both chemical compounds, and the pharmaceutical form is a solution for infusion.

**Quofenix** is provided as 450 mg tablets, administered orally. The maximum daily dose is 0.9 g, with a total dose of 12.6 g over a 14-day treatment period. The active substance is **delafloxacin**, a chemical compound, and the pharmaceutical form is a tablet.

**CEFEPIME ACCORD** is available as a 1 g powder for solution for injection/infusion, administered intravenously. The maximum daily dose is 6 g, with a total dose of 84 g over a 14-day treatment period. The active substance is **cefepime**, a chemical compound, and the pharmaceutical form is a solution for injection/infusion.

**Imipenem/Cilastatina Aurovitas** is provided as a 500 mg/500 mg powder for solution for infusion, administered intravenously. The maximum daily dose is 4 g, with a total dose of 56 g over a 14-day treatment period. The active substances are **cilastatin sodium** and **imipenem monohydrate**, both chemical compounds, and the pharmaceutical form is a solution for infusion.

**Azactam** is available as a 1 g powder for solution for injection or infusion, administered intravenously. The maximum daily dose is 8 g, with a total dose of 112 g over a 14-day treatment period. The active substance is **aztreonam**, a chemical compound, and the pharmaceutical form is a solution for injection/infusion.

**Ciprofloxacino cinfa** is provided as 750 mg coated tablets, administered orally. The maximum daily dose is 1.5 g, with a total dose of 10.5 g over a 7-day treatment period. The active substance is **ciprofloxacin**, a chemical compound, and the pharmaceutical form is a coated tablet.

**Quofenix** is available as 450 mg tablets, administered orally. The maximum daily dose is 0.9 g, with a total dose of 6.3 g over a 7-day treatment period. The active substance is **delafloxacin**, a chemical compound, and the pharmaceutical form is a tablet.

**Zerbaxa** is provided as a 1 g/0.5 g powder for concentrate for solution for infusion, administered intravenously. The maximum daily dose is 9 g, with a total dose of 63 g over a 7-day treatment period. The active substances are **tazobactam** and **ceftolozane**, both chemical compounds, and the pharmaceutical form is a solution for infusion.

**Piperacilina/Tazobactam Sala** is available as a 4 g/0.5 g powder for solution for infusion, administered intravenously. The maximum daily dose is 13.5 g, with a total dose of 94.5 g over a 7-day treatment period. The active substances are **piperacillin** and **tazobactam**, both chemical compounds, and the pharmaceutical form is a solution for infusion.

**CIPROFLOXACINO KABI** is provided as a 2 mg/ml solution for infusion, administered intravenously. The maximum daily dose is 1.2 g, with a total dose of 8.4 g over a 7-day treatment period. The active substance is **ciprofloxacin**, a chemical compound, and the pharmaceutical form is a solution for infusion.

**AMIKACINE B. BRAUN** is available as a 2.5 mg/ml solution for infusion, administered intravenously. The maximum daily dose is 3.6 g, with a total dose of 50.4 g over a 14-day treatment period. The active substance is **amikacin**, a chemical compound, and the pharmaceutical form is a solution for infusion.

**Zerbaxa** is provided as a 1 g/0.5 g powder for concentrate for solution for infusion, administered intravenously. The maximum daily dose is 9 g, with a total dose of 126 g over a 14-day treatment period. The active substances are **tazobactam** and **ceftolozane**, both chemical compounds, and the pharmaceutical form is a solution for infusion.

**Vaborem** is provided as a 1 g/1 g powder for concentrate for solution for infusion, administered intravenously. The maximum daily dose is 12 g, with a total dose of 84 g over a 7-day treatment period. The active substances are **meropenem** and **vaborbactam**, both chemical compounds, and the pharmaceutical form is a solution for infusion.

**Fetcroja** is available as a 1 g powder for concentrate for solution for infusion, administered intravenously. The maximum daily dose is 3 g, with a total dose of 21 g over a 7-day treatment period. The active substance is **cefiderocol**, a chemical compound, and the pharmaceutical form is a solution for infusion.

**Zavicefta** is provided as a 2 g/0.5 g powder for concentrate for solution for infusion, administered intravenously. The maximum daily dose is 7.5 g, with a total dose of 52.5 g over a 7-day treatment period. The active substances are **ceftazidime** and **avibactam**, both chemical compounds, and the pharmaceutical form is a solution for infusion.

**Levofloxacino Kabi** is available as a 5 mg/ml solution for infusion, administered intravenously. The maximum daily dose is 1 g, with a total dose of 7 g over a 7-day treatment period. The active substance is **levofloxacin hemihydrate**, a chemical compound, and the pharmaceutical form is a solution for infusion.

**Cefepima Accord** is provided as a 1 g powder for solution for injection/infusion, administered intravenously. The maximum daily dose is 6 g, with a total dose of 42 g over a 7-day treatment period. The active substance is **cefepime**, a chemical compound, and the pharmaceutical form is a solution for injection/infusion.

**Ceftazidima SALA** is available as a 1,000 mg powder for solution for infusion, administered intravenously. The maximum daily dose is 6 g, with a total dose of 42 g over a 7-day treatment period. The active substance is **ceftazidime**, a chemical compound, and the pharmaceutical form is a solution for injection.

Efficacy

The efficacy of the clinical trial will be assessed using both primary and secondary endpoints. The primary endpoint involves evaluating the days of antibiotic treatment and the category on the DOOR (Desirability of Outcome Ranking) scale at the end of follow-up, specifically on Day +30 after the completion of appropriate antibiotic treatment. This assessment aims to determine the effectiveness of a 7-day antibiotic regimen compared to a 14-day regimen in treating **Pseudomonas aeruginosa** bacteremia.

Secondary endpoints include all-cause mortality, clinical cure, and treatment failure, which will be measured on Days +30 and +90 post-treatment. Additionally, the trial will monitor superinfections, serious adverse events, days of hospital stay, and recurrences (proven, probable, or possible) on Day +90 after the end of the appropriate antibiotic treatment. These endpoints will provide a comprehensive evaluation of the treatment's efficacy and safety profile.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Adult patients (18 years or older).
Present bacteremia due to P. aeruginosa.
Having received 6 days (+/-1) of active antibiotic treatment against bacteremia counted from the date of extraction of the first positive blood culture and until the moment of randomization.
Have signed the informed consent for the trial.

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Exclusion Criteria

Minors under 18 years of age.
Pregnant or breastfeeding women. Potentially fertile patients must have a negative pregnancy test.
Focus of bacteremia not adequately controlled at least 72 hours before randomization.
Bacteremia secondary to an infection that necessarily requires prolonged antibiotic treatment, greater than 7 days, including: -Post-obstructive or necrotizing pneumonia. -Lung abscesses. -Acute prostatitis. -Bone and joint infections. -Central nervous system infections. -Endovascular infections related to vascular prostheses. -Any other at the discretion of the doctor responsible for the patient.
Coexistence of a different infection at the time of diagnosis of bacteremia that also requires antibiotic treatment if their treatment will be extended beyond 7 days from the diagnosis of bacteremia by P. aeruginosa. On the contrary, in the event that an infection coexists whose treatment ends before randomization, the patient may be included. Also in case there are isolates other than P. aeruginosa in samples corresponding to colonizations that do not require antibiotic treatment (asymptomatic bacteriuria, contamination of blood cultures by colonizers usual, bronchoaspirates without symptoms or signs suggestive of infection respiratory), the patient may be included in the trial..
Bacteremic pneumonia in severely immunocompromised patients, defined as: -Patients with severe neutropenia (<500 cells/mm3). -Recipients of allogeneic hematopoietic stem cell or solid organ transplant, during the first year after the transplant. -Active graft-versus-host disease requiring immunosuppressive treatment. -Patients with solid tumors who are receiving chemotherapy. -Untreated HIV infection with CD4 < 200 cells/mm3. -Patients with primary combined immunodeficiency. -Steroid treatment with prednisone > 20 mg/day (or equivalent) for 14 days prior to randomization.
Bacteremia of any origin in patients with severe neutropenia (<500 cells/mm3) at the time of randomization.
Bacteremia of any origin in large burns.
Bacteremia produced by strains resistant to all beta-lactams and quinolones.
Polymicrobial bacteremia including microorganisms other than P. aeruginosa. Polymicrobial bacteremia is considered the isolation in blood of more than one bacteria other than P.aeruginosa with clinical significance. P.aeruginosa bacteremias that are accompanied by isolates considered as contaminations (coagulase-negative staphylococci or viridans group streptococci, etc.) without clinical significance can be recruited for the trial, since these will not require specific treatment, and should not be considered polymicrobial bacteremia for the purposes of the assay.
Patients in palliative care or with an expected survival of less than 48 hours at the time of randomization.
Bacteremia due to P. aeruginosa in the previous 30 days as long as the previous infection has not been resolved.
The doctor responsible for the patient does not want to include the patient in the clinical trial.

Trial Status by Country

Country	Status	Start of Recruitment	Planned Patients
Spain	Not Recruiting	20 May 2022	306

Sites & Investigators

Research sites

Hospital Vall d’Hebron Hospital Universitario da A Coruna Parc Tauli Hospital Universitari Virgen del Rocío University Hospital

Investigators

Jose Ramon P. P.Aina G.Helem Haydee V. R.Luis Eduardo L. C.

Investigational Products

Details about the medicinal products being studied in this clinical trial.

Product Name	Role in Trial	Formulation	Administration	Max Daily Dose	Treatment Duration	EU MP Number
Zerbaxa 1 g/0.5 g powder for concentrate for solution for infusion	Test	POWDER FOR CONCENTRATE FOR SOLUTION FOR INFUSION	INTRAVENOUS	9	7	PRD6367587
Azactam 1g polvo para solución inyectable	Test	POLVO PARA SOLUCIÓN INYECTABLE	INTRAVENOUS	8	7	PRD390109
Ceftazidima SALA 1.000 mg polvo para solución para perfusión EFG	Test	POLVO PARA SOLUCIÓN PARA PERFUSIÓN	INTRAVENOUS	6	7	PRD353937
Meropenem Qilu 1 g polvo para solución inyectable y para perfusión EFG	Test	POLVO PARA SOLUCIÓN INYECTABLE Y PARA PERFUSIÓN	INTRAVENOUS	6	7	PRD10354376
Colistimetato de sodio Accord 2 millones de UI polvo para solución inyectable y para perfusión EFG	Comparator	POLVO PARA SOLUCIÓN INYECTABLE Y PARA PERFUSIÓN	INTRAVENOUS	9	14	PRD4089815
Zerbaxa 1 g/0.5 g powder for concentrate for solution for infusion	Comparator	POWDER FOR CONCENTRATE FOR SOLUTION FOR INFUSION	INTRAVENOUS	9	14	PRD6367589
MEROPENEM QILU 1 g, poudre pour solution injectable/pour perfusion	Comparator	POUDRE POUR SOLUTION INJECTABLE/POUR PERFUSION	INTRAVENOUS	6	14	PRD10138989
Quofenix 300 mg powder for concentrate for solution for infusion	Comparator	POWDER FOR CONCENTRATE FOR SOLUTION FOR INFUSION	INTRAVENOUS	0.6	14	PRD7784465
CIPROFLOXACINO KABI 2 mg/ml solución para perfusion	Test	SOLUCIÓN PARA PERFUSIÓN	INTRAVENOUS	1.2	7	PRD409000
Fetcroja 1 g powder for concentrate for solution for infusion	Comparator	POWDER FOR CONCENTRATE FOR SOLUTION FOR INFUSION	INTRAVENOUS	3	14	PRD8031117

Aztreonam

11 trials

Also investigated for

Urinary tract infection 5 Abdominal infection 3 Pneumonia 3 Bacterial infection 2