Antibiotics for Delirium

(A-DONUT Trial)

Recruiting at 7 trial locations

Overseen By Michael Fralick, MD

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: Mount Sinai Hospital, Canada

Must not be taking: Fosfomycin

Disqualifiers: Fever, Urinary symptoms, Catheter, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: Up to 7 days or until hospital discharge

550 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether antibiotics can treat delirium in hospitalized older adults who might have an infection. Delirium, a sudden state of confusion, often links to infections, but determining if antibiotics help when bacteria are found in urine is challenging. Participants will join one of two groups: one receiving antibiotics and the other not. This trial suits individuals aged 60 or older who are hospitalized with delirium and have bacteria in their urine, but no fever or recent antibiotic treatment. As an unphased trial, it offers participants the chance to contribute to important research that could enhance treatment for delirium in older adults.

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. However, it mentions that participants should have had less than 24 hours of antibiotics before the trial assessment.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research shows that using antibiotics in older adults poses safety challenges. As people age, their bodies change, and they might already take several medications, increasing the risk of side effects. Studies have found that antibiotics can sometimes cause unexpected issues like confusion or hallucinations. For instance, antibiotics such as azithromycin and clarithromycin have been linked to confusion starting just a few days after use. While antibiotics often treat infections, evidence does not clearly show they improve confusion in older adults when bacteria is found in their urine. Therefore, while antibiotics can be useful for treating infections, their safety in addressing confusion remains uncertain, especially in older adults. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Researchers are excited about using antibiotics for delirium because this approach explores a potential link between infections and mental confusion, particularly in cases related to urinary tract infections. Unlike traditional treatments for delirium, which focus on managing symptoms with antipsychotics or sedatives, antibiotics target the underlying infection that might be contributing to the condition. This method could offer a more direct and potentially faster way to alleviate delirium by addressing one of its possible root causes. If successful, this could change how we think about and treat delirium, especially when it's linked to infections.

What evidence suggests that antibiotics might be an effective treatment for delirium?

This trial will compare the use of antibiotics to no antibiotics for delirium in older adults. Research has shown that antibiotics do not improve confusion (delirium) in older adults with bacteria in their urine. A detailed review found no proof of antibiotics' effectiveness for delirium in these cases. Some studies suggest that antibiotics might cause side effects, such as nerve problems, which can worsen confusion. In very sick patients, antibiotics did not reduce the chances of delirium. Overall, current evidence does not support using antibiotics as a treatment for delirium in older adults. ^{1 4 6 7 8}

Who Is on the Research Team?

Michael Fralick, MD, PhD

Principal Investigator

Sinai Health System

Chris Kandel, MD, PhD

Principal Investigator

Michael Garron Hospital

Nathan Stall, MD, PhD

Principal Investigator

Sinai Health System

Are You a Good Fit for This Trial?

This trial is for adults aged 60 or older who are hospitalized with active delirium but do not have clear symptoms of a urinary tract infection. They must have had less than 24 hours of antibiotics before the trial and show signs of bacteria or white blood cells in their urine. Those with fever, UTI symptoms, long-term catheters, or other reasons for antibiotic use can't join.

Inclusion Criteria

You have signs of infection in your urine.

I have taken antibiotics for less than 24 hours before the trial assessment.

You are currently experiencing confusion and disorientation, as diagnosed by a doctor or using a specific assessment tool.

Exclusion Criteria

I have not had a fever higher than 100.2F in the last 2 days.

I am experiencing symptoms of a urinary tract infection.

The doctor has a reason to give you antibiotics other than delirium and urine test results.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

1-2 weeks

Treatment

Participants are randomized to receive either antibiotics or no antibiotics to assess the impact on delirium

Up to 7 days or until hospital discharge

Daily monitoring during hospital stay

Follow-up

Participants are monitored for safety and effectiveness after treatment, including assessment for C. difficile infection

30 days

What Are the Treatments Tested in This Trial?

Interventions

• Antibiotics

Trial Overview The study aims to determine if giving antibiotics to older adults with delirium and suspected infection (due to bacteria in urine) helps improve their condition. It's a randomized controlled trial where some patients will receive antibiotics while others won't, to compare outcomes.

How Is the Trial Designed?

Group I: No Antibiotics Experimental Treatment 1 Intervention

Participants will be randomized to no antibiotics

Group II: Antibiotics Experimental Treatment 1 Intervention

Participants will be randomized to start or continue with antibiotics. Antibiotic type and duration targeted to lower urinary tract infection as directed by the Most Responsible Physician (MRP).

Antibiotics is already approved in United States, European Union, Canada for the following indications:

Approved in United States as Antibiotics for:

• Appendicitis
• Intra-abdominal infections
• Surgical site infections

Approved in European Union as Antibiotics for:

• Appendicitis
• Intra-abdominal infections
• Surgical site infections

Approved in Canada as Antibiotics for:

• Appendicitis
• Intra-abdominal infections
• Surgical site infections

Who Is Running the Clinical Trial?

Mount Sinai Hospital, Canada

Lead Sponsor

Trials

210

Recruited

70,700+

Northwestern Memorial Hospital

Collaborator

Trials

42

Recruited

15,800+

Sault Area Hospital

Collaborator

Trials

5

Recruited

1,100+

Michael Garron Hospital

Collaborator

Trials

16

Recruited

7,200+

Unity Health Toronto

Collaborator

Trials

572

Recruited

470,000+

The Ottawa Hospital

Collaborator

Trials

97

Recruited

64,000+

Published Research Related to This Trial

Diclofenac was found to be the most effective anti-inflammatory agent against Brucella spp., with a minimum inhibitory concentration (MIC90) of 16 micrograms/ml, indicating its potential as a treatment option.

Among the phenothiazine derivatives and antidepressants tested, sertraline showed significant antimicrobial activity with an MIC90 of 16 micrograms/ml, while diazepam was much less effective, highlighting the variability in efficacy among these agents.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

In vitro activity of nonsteroidal anti-inflammatory agents, phenotiazines, and antidepressants against Brucella species. Muñoz-Criado, S., Muñoz-Bellido, JL., García-Rodríguez, JA.[2019]

A review of 25 studies found that common cognitive side effects from various antimicrobials include confusion, delirium, and impaired attention, highlighting the need for awareness among healthcare providers.

Risk factors for these cognitive impairments often include older age and renal impairment, and the mechanisms of these side effects can vary by antimicrobial class, suggesting tailored management strategies are necessary.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antimicrobial-induced cognitive side effects. Warstler, A., Bean, J.[2022]

Delirium is a common and serious complication in hospitalized elderly patients, often going unrecognized by clinicians in up to 70% of cases, which can lead to increased morbidity and mortality.

Levofloxacin, a commonly used antibiotic, has been associated with delirium in elderly patients, with only eight reported cases in the literature, indicating that this adverse effect may be more prevalent than previously thought and highlighting the need for greater awareness among healthcare providers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Delirium induced by levofloxacin. Odeh, M., Kogan, Y., Paz, A., et al.[2019]

Levofloxacin, a commonly used antibiotic, can induce delirium in elderly patients, highlighting a serious and often underrecognized side effect.

This case adds to the limited literature on levofloxacin-induced delirium, emphasizing the need for increased awareness among healthcare providers regarding this potential adverse effect in hospitalized elderly patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acute Delirium Associated With Levofloxacin. Kogan, Y., Elias, N., Paz, A., et al.[2020]

Antibiotics, commonly prescribed in the U.S., can have significant effects on the central nervous system, leading to psychiatric side effects such as anxiety, depression, and psychosis, regardless of a patient's prior mental health history.

Factors like age, existing medical conditions, and interactions with other medications can increase the risk of these psychiatric effects, highlighting the need for clinicians to be aware of these potential side effects when prescribing antibiotics.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antibiotics: neuropsychiatric effects and psychotropic interactions. Sternbach, H., State, R.[2019]

Delirium has been reported in patients taking macrolide antibiotics such as clarithromycin, azithromycin, erythromycin, and telithromycin, affecting various age groups including children.

The average onset of delirium was 2.5 days for azithromycin and 3.3 days for clarithromycin, highlighting the importance of timely recognition and discontinuation of these antibiotics to improve patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Delirium associated with the use of macrolide antibiotics: a review. Pejčić, AV.[2022]

A study analyzing over 10 million reports from the FDA Adverse Event Reporting System found that several antibiotics, including ertapenem, cefepime, and imipenem, are significantly associated with an increased risk of delirium, with ertapenem showing the highest risk (ROR 21.07).

The research highlights the importance of monitoring for delirium in patients receiving these antibiotics, as the findings suggest a need for caution when prescribing these medications due to their potential neuropsychiatric side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Delirium Associations with Antibiotics: A Pharmacovigilance Study of the FDA Adverse Event Reporting System (FAERS). Teng, C., Frei, CR.[2022]

Various classes of antimicrobials, particularly fluoroquinolones, macrolides, and β-lactams, have been linked to neurotoxic effects such as delirium and psychosis in geriatric patients, highlighting the need for careful monitoring in this vulnerable population.

Elderly patients are at a higher risk for neurotoxicity from specific antimicrobials, especially when they have renal dysfunction or are taking multiple medications, suggesting that clinicians should be vigilant about potential drug interactions and side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neurotoxicity with antimicrobials in the elderly: a review. Mattappalil, A., Mergenhagen, KA.[2018]

Most antibiotic side effects are linked to specific individual agents rather than to the class of antibiotics as a whole, highlighting the importance for clinicians to understand the unique side effects of each medication.

While most adverse reactions are reversible upon stopping the antibiotic, some can lead to serious and irreversible conditions, such as ototoxicity from aminoglycosides and Stevens-Johnson syndrome, emphasizing the need for careful medication management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antibiotic side effects. Cunha, BA.[2022]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/38895992/

Antibiotics for delirium in older adults with pyuria or ... Conclusions: Our systematic review found no evidence that treatment with antibiotics is associated with improved delirium outcomes in older adults with pyuria ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6291937/

Antimicrobial exposure and the risk of delirium in critically ill ... Of 418 ICU patients, delirium occurred in 308 (74%) with a median of 3 days (interquartile range 2–6) among those affected and 318 (76%) were ...

3. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0149291814006122

Neurotoxicity with Antimicrobials in the Elderly: A Review Neurotoxic adverse effects, such as delirium and psychosis, are unexpected and unpredictable. Symptoms can easily be mistaken for manifestations ...

4. e-jhpc.org e-jhpc.org/journal/view.html?doi=10.14475/jhpc.2024.27.3.99

Ethical and Practical Issues with the Use of Antimicrobial ... Other studies have reported that up to 84% of patients received antimicrobials near the EOL [4]. The most rigorous study identified was ...

5. mdpi.com mdpi.com/2227-9059/11/6/1633

Pharmacokinetics of Antibacterial Agents in the Elderly High rates of consumption of antimicrobial agents by the elderly may result in increased risk of toxic reactions, deteriorating functions of various organs and ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10043546/

Safety and Tolerability of Antimicrobial Agents in the Older ... Older patients using antimicrobials have a higher risk of ADRs due to age-related changes in PK and PD, multimorbidity, and polypharmacy.

7. agsjournals.onlinelibrary.wiley.com agsjournals.onlinelibrary.wiley.com/doi/10.1111/jgs.18964

Antibiotics for delirium in older adults with pyuria or bacteriuria ... Our systematic review found no evidence that treatment with antibiotics is associated with improved delirium outcomes in older adults with ...

8. tandfonline.com tandfonline.com/doi/abs/10.1080/13651501.2020.1828933

Delirium associated with the use of macrolide antibiotics Time to onset of delirium ranged from 2 to 3.5 days (mean: 2.5 days) for azithromycin and from 1 to 7 days (mean: 3.3 days) for clarithromycin. Cessation of the ...