Antibiotics for Staph Infection

(SNAP Trial)

Recruiting at 177 trial locations

Overseen By Susan Goulding

Age: Any Age

Sex: Any

Trial Phase: Phase 4

Sponsor: University of Melbourne

Must not be taking: Clindamycin, Linezolid

Disqualifiers: Polymicrobial bacteraemia, Severe allergies, Dialysis, others

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

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 1

Duration: 5-14 days

8000 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores different antibiotic treatments to determine which best reduces mortality in people with a blood infection caused by Staphylococcus aureus, a common type of bacteria. Participants will receive various treatments, including cefazolin, clindamycin, penicillin, and vancomycin, and may undergo a PET/CT scan to guide treatment. Ideal candidates for this trial are those who have recently tested positive for a Staphylococcus aureus blood infection while hospitalized. As a Phase 4 trial, the treatments are already FDA-approved and proven effective, and this research aims to understand how they benefit more patients.

Do I need to stop my current medications for the trial?

The trial does not specify if you need to stop taking your current medications. However, if you are currently on certain antibiotics that cannot be stopped or substituted, you may not be eligible for some parts of the trial.

What is the safety track record for these treatments?

Previous studies have shown cefazolin to be safe. It has long been used to prevent and treat infections and is generally well-tolerated at various doses. Research indicates that cefazolin can effectively and safely clear infections, even in high amounts.

Research shows that clindamycin is FDA-approved for treating several serious infections. It works well against certain bacteria, including Staphylococcus aureus. While generally safe, clindamycin can cause allergic reactions in some individuals and should be used cautiously in those with a history of such reactions.

Penicillin is well-known for treating infections caused by Staphylococcus aureus. Studies suggest it is safe and effective, especially for strains responsive to penicillin. However, some individuals may experience allergic reactions to penicillin.

Lastly, vancomycin is another option for treating Staphylococcus aureus infections. It is effective, but some studies show it can have more side effects compared to other antibiotics, often requiring monitoring to ensure safety.

In summary, these antibiotics have been used safely in many cases. However, individual reactions can vary, so personal health history and potential allergies should be considered. ^{1 2 3 4 5}

Why are researchers enthusiastic about this study treatment?

Researchers are excited about these treatments for Staph infections because they offer a variety of innovative approaches compared to standard care options like flucloxacillin, cloxacillin, vancomycin, and daptomycin. Unlike current treatments, some trial arms explore switching from intravenous to oral antibiotics after a week, which could simplify the treatment process and improve patient comfort and adherence. Another interesting aspect is the use of PET/CT scans to assess treatment efficacy early on, potentially allowing for quicker adjustments to therapy. Additionally, the trial investigates adjunctive therapies that combine standard treatments with new agents like clindamycin, aiming to enhance the overall effectiveness against resistant strains like MRSA. These advancements could lead to more efficient, adaptable, and comprehensive treatment strategies for Staph infections.

What evidence suggests that this trial's treatments could be effective for Staph infections?

In this trial, participants will receive different treatments for Staph infections. Cefazolin, which participants may receive, has proven very effective in previous studies for treating infections caused by methicillin-susceptible Staphylococcus aureus (MSSA), reducing the risk of death and recurring infections compared to other treatments. Clindamycin, another treatment option, has been associated with no deaths in severe Staphylococcus infections when added to treatment, making it a strong option for reducing fatalities. Penicillin, particularly benzylpenicillin, is also under study and has performed well for infections caused by penicillin-susceptible Staphylococcus aureus (PSSA) without a higher rate of treatment failure compared to other antibiotics. Vancomycin, included in this trial, is generally effective for Staphylococcus aureus infections, though it might have a slightly higher chance of side effects. Overall, research shows these antibiotics effectively treat different types of Staph infections. ^{6 7 8 9 10}

Who Is on the Research Team?

Prof Steven Tong

Principal Investigator

University of Melbourne / Melbourne Health

Prof Joshua Davies

Principal Investigator

Menzies School of Research / Hunter New England Medical Centre

Are You a Good Fit for This Trial?

This trial is for patients with a Staphylococcus aureus infection in their blood, who are currently admitted to a hospital participating in the study. It's not specified who can't join because the exclusion criteria are missing.

Inclusion Criteria

Admitted to a participating hospital at the time of eligibility assessment

Day 14 (+/- 2 days): Clearance of SAB by platform Day 5: blood cultures negative for S. aureus from platform Day 5 (+/-1 day) AND no known subsequent positive blood cultures. If the most recent blood culture from Day 2-4 is negative for S. aureus, blood cultures do not need to be repeated on Day 5 to fulfil eligibility criteria (Day 5 blood cultures will be assumed to be negative in this situation) Afebrile (<37.8°C) for the past 72 hours (at time of judging eligibility) Site Principal Investigator has determined that source control is adequate

My infection is clearing, I've been fever-free for 3 days, and any infection source has been treated.

Exclusion Criteria

I am under 18 and the site does not approve pediatric patients.

Clinician deems not appropriate for early oral switch

Severe allergy to any beta-lactam (including cefazolin)

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

1-2 weeks

1 visit (in-person)

Treatment

Participants receive intravenous antibiotics with potential switch to oral antibiotics based on eligibility at Day 7 or Day 14

5-14 days

Daily monitoring (in-patient)

Follow-up

Participants are monitored for safety and effectiveness after treatment, with primary endpoint being all-cause mortality at 90 days

90 days

Regular follow-up contacts

Sub-studies

Participants may be involved in additional sub-studies as part of the SNAP trial infrastructure

What Are the Treatments Tested in This Trial?

Interventions

• Cefazolin
• Clindamycin
• Effectiveness of early switch to oral antibiotics
• Penicillin
• Vancomycin

Trial Overview

The SNAP trial is testing several antibiotics (Penicillin, Clindamycin, Vancomycin, Cefazolin) and strategies like switching to oral antibiotics early on to see which reduces mortality in Staph bloodstream infections.

How Is the Trial Designed?

Group I: Switch to oral antibiotics at trial day 7 (+/- 2 days) or Day 14 (+/- 2 days) if eligible. Experimental Treatment 1 Intervention

Switch from intravenous backbone antibiotic for MRSA or MSSA or PSSA to oral antibiotics at the treating clinicians discretion on trial Day 7 (+/- 2 days) or trial Day 14 (+/- 2 days). Participants eligibility is assessed at Day 7 (+/- 2 days). If eligible will be randomised, if not eligible then eligibility will be assessed again at Day 14 (+/- 2 days). If eligibility is not met at day 14 then participant is excluded from this domain.

Group II: Penicillin-susceptible staphylococcus aureus (PSSA) - Interventional Arm (backbone therapy) Experimental Treatment 1 Intervention

Benzylpenicillin - Interventional Arm Intravenous benzylpenicillin 1.8g (3 million units) every 4 or 6 hours. The minimum protocol duration of allocated study treatment is 14 days for those not allocated to early oral switch, and 5 days for those allocated to early oral switch. For patients with critical illness the intravenous benzylpenicillin administration doses will be adjusted.

Group III: PET/CT scan at trial day 7 (+/- 2 days) if eligible Experimental Treatment 1 Intervention

Participant will receive a PET/CT scan at Day 5-12, in addition to their allocated treatment interventions. Participants eligibility is assessed at Day 7 (+/- 2 days) if eligible will be randomised. If eligibility is not met then participant is excluded from this domain.

Group IV: Methicillin-susceptible staphylococcus aureus (MSSA) - Interventional Arm (backbone therapy) Experimental Treatment 1 Intervention

Cefazolin - Interventional Arm Intravenous cefazolin 2g every 6 or 8 hours. The minimum protocol duration of allocated study treatment is 14 days for those not allocated to early oral switch, and 5 days for those allocated to early oral switch. For patients with renal impairment or critical illness the intravenous cefazolin administration dose will be adjusted.

Group V: Methicillin-resistant staphylococcus aureus (MRSA) - Standard + B-Lactam Arm (backbone therapy) Experimental Treatment 2 Interventions

Vancomycin or Daptomycin (Standard Therapy) + Beta-Lactam (β-lactam) Arm In addition to standard treatment an intravenous β-lactam will be added for the first 7 calendar days following randomisation (day 1 being the day of randomisation - hence patients will receive 6-7 days of β-lactam). This β-lactam will be intravenous cefazolin 2g every 8 hours. For patients with renal impairment the intravenous cefazolin administration doses will be adjusted.

Group VI: Adjunctive treatment in combination with MRSA or MSSA or PSSA backbone therapy arm Experimental Treatment 1 Intervention

Adjunctive therapy + backbone therapy arm for MRSA or MSSA or PSSA Intravenous clindamycin (or lincomycin) 600mg every 8 hours from platform day 1 to day 5. No dosage adjustment is needed to renal impairment.

Group VII: No PET/CT scan - standard of care arm Active Control 1 Intervention

Participants will not receive a PET/CT scan, in addition to their allocated treatment interventions. Participants eligibility is assessed at Day 7 (+/- 2 days) if eligible will be randomised. If eligibility is not met then participant is excluded from this domain.

Group VIII: Methicillin-susceptible staphylococcus aureus (MSSA) - Standard Therapy Arm (backbone therapy) Active Control 1 Intervention

Flucloxacillin or cloxacillin - Standard Therapy Arm Either intravenous flucloxacillin/cloxacillin 2g every 4 or 6 hours. The minimum protocol duration of allocated study treatment is 14 days for those not allocated to early oral switch, and 5 days for those allocated to early oral switch. For patients with renal impairment or critical illness the intravenous flucloxacillin administration dose will be adjusted.

Group IX: Penicillin-susceptible staphylococcus aureus (PSSA) - Standard Therapy Arm (backbone therapy) Active Control 1 Intervention

Flucloxacillin or cloxacillin - Standard Therapy Arm Either intravenous flucloxacillin/cloxacillin 2g every 4 or 6 hours. The minimum protocol duration of allocated study treatment is 14 days for those not allocated to early oral switch, and 5 days for those allocated to early oral switch. For patients with renal impairment or critical illness the intravenous flucloxacillin administration dose will be adjusted.

Group X: Methicillin-resistant staphylococcus aureus (MRSA) - Standard Therapy Arm (backbone therapy) Active Control 1 Intervention

Vancomycin or Daptomycin - Standard Therapy Arm Either intravenous vancomycin dosed as per Australian Therapeutic Guidelines: This includes a loading dose of 25 mg/kg (up to 3000mg) if considered appropriate by the treating clinician, initial maintenance dosing at 15-20 mg/kg q12h, with subsequent adjustment to maintain area under the concentration-time curve (AUC) of 400 to 600 mg.hr/L OR trough levels at 10-20 mg/L, and the initial level taken 48-72 hours after the initiation of the first dose. Daptomycin 8-10mg/kg per day intravenously. The choice of vancomycin or daptomycin will be at the clinician's discretion. Dosing will be based on renal function.

Group XI: Continue intravenous antibiotic therapies (backbone +/- adjunctive therapy) - standard of care arm Active Control 1 Intervention

Backbone therapy arm for MRSA or MSSA or PSSA +/- adjunctive therapy will continue on intravenous antibiotic treatment for the length of time as per usual standard of care. Participants eligibility is assessed at Day 7 (+/- 2 days) if eligible will be randomised if not eligible then eligibility will be assess again at Day 14(+/- 2 days). If eligibility is not met at day 14 then participant is excluded from this domain.

Group XII: No adjunctive treatment in combination with MRSA or MSSA or PSSA backbone therapy arm Active Control 1 Intervention

No adjunctive therapy + backbone therapy arm for MRSA or MSSA or PSSA Participants with either MRSA or MSSA or PSSA will have no adjunctive therapy in combination with their backbone therapy arm.

Who Is Running the Clinical Trial?

University of Melbourne

Lead Sponsor

Trials

193

Recruited

1,287,000+

King's College London

Collaborator

Trials

772

Recruited

26,130,000+

Rambam Health Care Campus

Collaborator

Trials

513

Recruited

350,000+

University College, London

Collaborator

Trials

884

Recruited

38,770,000+

Houston Medical Research Institute

Collaborator

Trials

1

Recruited

8,000+

Berry Consultants

Collaborator

Trials

16

Recruited

58,200+

Tan Tock Seng Hospital

Collaborator

Trials

152

Recruited

7,293,000+

Sunnybrook Health Sciences Centre

Collaborator

Trials

693

Recruited

1,569,000+

Telethon Kids Institute

Collaborator

Trials

16

Recruited

21,100+

The Peter Doherty Institute for Infection and Immunity

Collaborator

Trials

18

Recruited

15,300+

Published Research Related to This Trial

Beta-lactams, particularly penicillins, are the preferred choice for treating acute orofacial infections due to their effectiveness against common pathogens.

Macrolides, like azithromycin and clarithromycin, are gaining popularity for their low toxicity and ability to target intracellular microorganisms, while clindamycin serves as an alternative for patients allergic to penicillin.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antibiotics for acute orofacial infections. Pallasch, TJ.[2013]

A study of 833 Staphylococcus aureus strains from skin infections showed that no strains were resistant to vancomycin, indicating its continued effectiveness as a treatment option.

The incidence of methicillin-resistant Staphylococcus aureus (MRSA) was found to be between 10% and 20%, highlighting the ongoing challenge of antibiotic resistance in these infections.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Susceptibility change to antibiotics of Staphylococcus aureus strains isolated from skin infections between July 1994 and November 2000. Nishijima, S., Kurokawa, I., Nakaya, H.[2018]

In a study of over 6 million individuals, new penicillin allergies were reported more frequently after parenteral exposure (0.85%) compared to oral exposure (0.74%), indicating a higher risk of allergic reactions with injectable forms.

Anaphylaxis was rare, with only 22 cases associated with oral penicillin and 3 with parenteral penicillin, suggesting that while allergic reactions can occur, they are infrequent. Additionally, Clostridioides difficile infections were more common after parenteral antibiotic use, highlighting a potential safety concern with these treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse Reactions Associated with Penicillins, Carbapenems, Monobactams, and Clindamycin: A Retrospective Population-based Study. Liang, EH., Chen, LH., Macy, E.[2021]

In a study of 734 surgical procedures involving 690 patients labeled as penicillin allergic, the incidence of hypersensitivity reactions was low and similar across cefazolin, clindamycin, and vancomycin, suggesting that cefazolin can be safely used in these patients.

The study found that only 0.9% of patients receiving cefazolin experienced probable hypersensitivity reactions, indicating that avoiding cefazolin due to penicillin allergy concerns may not be necessary.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of immediate hypersensitivity reactions to preoperative antibiotics in patients labeled as penicillin allergic. Fosnot, S., Currier, K., Pendell, J., et al.[2021]

A study involving 200 children with perforated appendicitis found that four different antibiotic regimens had similar clinical and bacteriological efficacy, indicating that various combinations can be safely used.

No significant differences were observed in outcomes such as duration of fever, hospital stay, or complications, suggesting that all tested regimens effectively covered the predominant bacteria involved in the infection.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparative trial of four antibiotic combinations for perforated appendicitis in children. Ciftci, AO., Tanyel, FC., Büyükpamukçu, N., et al.[2013]

Methicillin-resistant Staphylococcus aureus (MRSA) infections are a significant clinical challenge, requiring specific treatment strategies such as parenteral vancomycin or teicoplanin for serious cases, while less serious infections can be managed with lincosamides or cotrimoxazole.

For multi-resistant MRSA strains (mrMRSA), a combination of oral antimicrobials like rifampicin and fusidic acid is necessary to prevent rapid resistance development, highlighting the importance of tailored antibiotic therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antibiotics currently used in the treatment of infections caused by Staphylococcus aureus. Rayner, C., Munckhof, WJ.[2006]

In a study assessing the effectiveness of ten antibiotics against both methicillin-susceptible and methicillin-resistant Staphylococcus isolates, clindamycin, along with vancomycin, cephalothin, and rifampicin, showed the highest activity.

Clindamycin may be particularly beneficial for treating infections caused by methicillin-resistant staphylococci due to its lower toxicity compared to vancomycin and its ability to enhance opsonization, which helps the immune system target bacteria.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Activity of several antibiotics against staphylococci. Aceti, A., Attanasio, R.[2013]

In a study of 20 patients with a history of type I hypersensitivity to penicillins, 18 showed negative skin test reactions to cephalosporin antibiotics, suggesting they can safely receive these medications for chemoprophylaxis during open heart surgery.

Only 2 patients had positive skin tests, but they were able to receive vancomycin safely, indicating that negative skin tests can help identify patients who are not at risk for allergic reactions to cephalosporins.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cross allergenicity between penicillins and cephalosporins. Beam, TR., Spooner, J.[2006]

In a systematic review of 6147 patients, only 0.7% had a dual allergy to cefazolin and natural penicillins, indicating that most patients with a history of penicillin allergy can safely receive cefazolin as a preoperative antibiotic.

Patients with confirmed penicillin allergies showed a higher dual allergy frequency of 3.0%, suggesting that extra caution is needed for this group when considering cefazolin administration.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Assessment of the Frequency of Dual Allergy to Penicillins and Cefazolin: A Systematic Review and Meta-analysis. Sousa-Pinto, B., Blumenthal, KG., Courtney, L., et al.[2022]

MK 0787 (N-formimidoyl thienamycin) demonstrated the highest activity against gram-positive cocci compared to cefotaxime, moxalactam, ampicillin, oxacillin, vancomycin, and clindamycin.

In cases of methicillin-resistant Staphylococcus aureus, vancomycin was the most effective treatment, while cefotaxime showed superior activity against penicillin-resistant pneumococci.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Susceptibility of gram-positive cocci to various antibiotics, including cefotaxime, moxalactam, and N-formimidoyl thienamycin. Cherubin, CE., Corrado, ML., Sierra, MF., et al.[2021]

In a review of adverse reactions to various antibacterial drugs involving over 5,000 patients, cefotaxime had the highest side effect rate at 9.8%, while cefazolin had the lowest at 3.8%, indicating varying safety profiles among these antibiotics.

No significant intergroup differences in serious adverse effects were found, and no deaths were attributed to any of the drugs, suggesting that while side effects occur, they are generally manageable and not life-threatening.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Update of safety of cefotaxime. Childs, SJ., Kosola, JW.[2013]

Clindamycin was found to be effective in treating invasive infections caused by community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) in children, indicating its potential as a treatment option.

In a study of 46 children with CA-MRSA and 53 with methicillin-susceptible Staphylococcus aureus (MSSA), the median duration of positive blood cultures was longer for MRSA patients, suggesting a more severe infection course compared to MSSA.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clindamycin treatment of invasive infections caused by community-acquired, methicillin-resistant and methicillin-susceptible Staphylococcus aureus in children. Martínez-Aguilar, G., Hammerman, WA., Mason, EO., et al.[2013]

There are currently seven effective drugs for treating infections caused by drug-resistant Staphylococcus aureus, including MRSA, with linezolid being the preferred choice for complicated skin and soft tissue infections, while daptomycin and telavancin also show strong efficacy.

Despite the availability of these treatments, challenges remain in effectively managing MRSA infections, as treatment failures still occur, highlighting the need for ongoing research and development of new antibiotics.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of infections due to resistant Staphylococcus aureus. Anstead, GM., Cadena, J., Javeri, H.[2013]

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The results indicate that compared to ASPs, cefazolin was associated with significant reduction in mortality (OR, 0.69; 95% CI, 0.58 to 0.82; I 2 = 3.4%) and ...

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Management of Staphylococcus aureus Infections

Although the incidence of complex S. aureus infections is rising, new antimicrobial agents, including daptomycin and linezolid, are available as treatment.