Antibiotics for Delirium

(A-DONUT Trial)

Recruiting at 7 trial locations

Overseen by Nathan Stall, MD, PhD

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Academic

Recruiting

Sponsor: Mount Sinai Hospital, Canada

Must not be taking: Fosfomycin

Disqualifiers: Fever, Urinary symptoms, Catheter, others

No Placebo Group

Approved in 3 Jurisdictions

Trial Summary

What is the purpose of this trial?

Delirium is an acute confusional state that is experienced by many older adults who are admitted to hospital. To treat delirium the underlying cause needs to be identified promptly, but this is challenging. One of the potential causes of delirium is infection. Urine tests show that most patients experiencing delirium have bacteria in their urine, however, bacteria in the urine is common among older adults, and does not automatically indicate an infection is present. As a result it is difficult to know whether a lower urinary tract infection is present as individuals with delirium are frequently unable to report clinical signs of infection - symptoms of pain or discomfort with urination, having to urinate more frequently or pelvic discomfort. Very often, individuals with delirium are treated with antibiotics despite the fact that it is unknown whether antibiotics help to improve delirium in cases where bacteria in the urine is present. This proposed study is a randomized controlled trial that will examine if adults (age 60 or older) with delirium and suspected infection benefit from taking antibiotics.

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 it safe to use antibiotics for delirium?

Some antibiotics have been linked to delirium and other cognitive side effects, especially in older adults. These effects are often unpredictable and can vary depending on the specific antibiotic used. ^{1 2 3 4 5}

How do antibiotics differ from other drugs for treating delirium?

Antibiotics are unique in treating delirium because they are not typically used for this condition, and some antibiotics like levofloxacin have been associated with causing delirium as a side effect. This makes their use in treating delirium novel, as they are usually known for treating infections rather than neuropsychiatric conditions. ^{5 6 7 8 9}

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

Eligibility Criteria

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.

Trial Timeline

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

Treatment Details

Interventions

• Antibiotics (Anti-infective)

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.

Participant Groups

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 Canada for the following indications:

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+

Findings from Research

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]

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]

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]

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]

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]

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]

References

1. United States pubmed.ncbi.nlm.nih.gov

Antibiotic side effects. [2022]

2. England pubmed.ncbi.nlm.nih.gov

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

3. United States pubmed.ncbi.nlm.nih.gov

Antimicrobial-induced cognitive side effects. [2022]

4. United States pubmed.ncbi.nlm.nih.gov

Neurotoxicity with antimicrobials in the elderly: a review. [2018]

5. Switzerland pubmed.ncbi.nlm.nih.gov

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

6. Scotland pubmed.ncbi.nlm.nih.gov

Delirium induced by levofloxacin. [2019]

7. Germany pubmed.ncbi.nlm.nih.gov

In vitro activity of nonsteroidal anti-inflammatory agents, phenotiazines, and antidepressants against Brucella species. [2019]

8. Canada pubmed.ncbi.nlm.nih.gov

Acute Delirium Associated With Levofloxacin. [2020]

9. United States pubmed.ncbi.nlm.nih.gov

Antibiotics: neuropsychiatric effects and psychotropic interactions. [2019]