Probability of Target Attainment With Standard Intermittent Bolus Administration of Cefazolin in Patients With Complicated Infections Caused by Staphylococcus Aureus

NCT04503252 | Completed

• 1 other identifier: 2019-02229; me20Osthoff2
• Study Type: observational
• Target: 50
• Locations: 1 country
• Sites: 1

Brief Summary

Given the paucity of pharmacological data on cefazolin treatment of Methicillin-susceptible S. aureus (MSSA) complicated S. aureus infection (CSAI), the primary purpose of this study is to investigate the probability of pharmacological target attainment (in the blood and infected tissue) with standard intermittent bolus administration of cefazolin in patients with CSAI caused by MSSA by determining plasma concentrations of cefazolin and exact Minimum inhibitory concentration (MICs) of the causative MSSA strains in patients with various disease severities (e.g. critically ill vs. noncritically ill patients).

• Sub-study quantitative measurement of Torque Teno virus (TTV): The primary purpose of this sub-study is to describe the viral kinetics of TTV in CSAI patients and to explore the association of TTV viremia with clinical outcomes and molecular markers of activation of the immune system.
• Sub-study investigating antibiotic concentrations in sweat as a non-invasive therapeutic drug monitoring

Conditions

Staphylococcus Aureus Infection

Keywords

Bloodstream infection (BSI); Minimum inhibitory concentration (MIC); Methicillin-susceptible S. aureus (MSSA); Staphylococcus aureus (S. aureus); β-lactam antibiotics; flucloxacillin; cefazolin; pharmacological target attainment; Torque Teno virus (TTV); Therapeutic drug monitoring (TDM); antibiotic sweat concentrations; Complicated S. aureus infection (CSAI)

Outcome Measures

Primary Outcomes (7)

• Trough concentration of cefazolin in plasma samples

  Trough concentration of cefazolin measured in plasma samples

  1st (mid-dose and trough sample), 3rd (mid-dose and trough sample),7th and 14th day (for both only trough sample) of cefazolin treatment (+/-1-5 day) and if applicable in weekly intervals during outpatient parenteral antibiotic treatment (within 4 weeks)

• Total plasma concentrations of cefazolin in plasma samples

  Total plasma concentrations of cefazolin in plasma samples

  1st (mid-dose and trough sample), 3rd (mid-dose and trough sample) of cefazolin treatment (+/-1-5 day) and if applicable in weekly intervals during outpatient parenteral antibiotic treatment (within 4 weeks)

• Free drug concentrations of cefazolin in plasma samples

  Free drug concentrations of cefazolin in plasma samples

  1st (mid-dose and trough sample), 3rd (mid-dose and trough sample) of cefazolin treatment (+/-1-5 day) and if applicable in weekly intervals during outpatient parenteral antibiotic treatment (within 4 weeks)

• Trough concentration of cefazolin in sweat samples

  Trough concentration of cefazolin measured in sweat samples

  1st, 3rd,7th and 14th day of cefazolin treatment (+/-1-5 day) and if applicable in weekly intervals during outpatient parenteral antibiotic treatment (within 4 weeks)

• Total sweat concentrations of cefazolin

  Total sweat concentrations of cefazolin

  1st, 3rd,7th and 14th day of cefazolin treatment (+/-1-5 day) and if applicable in weekly intervals during outpatient parenteral antibiotic treatment (within 4 weeks)

• Free drug concentrations of cefazolin in sweat samples

  Free drug concentrations of cefazolin in sweat samples

  1st, 3rd,7th and 14th day of cefazolin treatment (+/-1-5 day) and if applicable in weekly intervals during outpatient parenteral antibiotic treatment (within 4 weeks)

• Target attainment (100%fT>MIC)

  Antibiotic susceptibility of the isolated pathogens determined by the use of an Minimum inhibitory concentration (MIC) test strip. Target attainment (100%fT\>MIC) will be calculated for each patient and for each day the patient was sampled. Target attainment is defined as a measured free trough plasma concentration of cefazolin above the measured exact MICs of the causative pathogens at all points of time sampled.

  1st, 3rd,7th and 14th day of cefazolin treatment (+/-1-5 day) and if applicable in weekly intervals during outpatient parenteral antibiotic treatment (within 4 weeks)

Secondary Outcomes (5)

• Pharmacological target attainment (100%fT>MIC) in infected tissue

  1st, 3rd,7th and 14th day of cefazolin treatment (+/-1-5 day) and if applicable in weekly intervals during outpatient parenteral antibiotic treatment (within 4 weeks)

• Attainment of an accepted threshold for toxicity (100%fT>10xMIC) in blood

  1st, 3rd,7th and 14th day of cefazolin treatment (+/-1-5 day) and if applicable in weekly intervals during outpatient parenteral antibiotic treatment (within 4 weeks)

• Level of cefazolin tolerance of the isolated pathogen

  1st, 3rd,7th and 14th day of cefazolin treatment (+/-1-5 day) and if applicable in weekly intervals during outpatient parenteral antibiotic treatment (within 4 weeks)

• TTV substudy: quantification of DNA

  1st, 3rd,7th and 14th day of cefazolin treatment (+/-1-5 day) and if applicable in weekly intervals during outpatient parenteral antibiotic treatment (within 4 weeks)

• TTV substudy: quantification of cytokines

  1st, 3rd,7th and 14th day of cefazolin treatment (+/-1-5 day) and if applicable in weekly intervals during outpatient parenteral antibiotic treatment (within 4 weeks)

Study Arms (3)

Study population: patients with CSAI caused by MSSA

Inpatients with CSAI caused by MSSA treated or intended to receive cefazolin within the next 24-48 hours (at least 10 (maximum of 20) critically-ill patients, at least 10 (maximum of 20) patients with an estimated glomerular filtration rate of \<60ml/min, at least 10 patients with BSI).

Other: Blood samples for the measurement of the concentration of cefazolin; Other: S. aureus culture isolate; Other: structured telephone interview

Sub-study: Torque Teno virus (TTV) viremia

TTV viral load may indicate the immunological status of the host. The TTV sub-study is to to describe the viral kinetics of TTV in CSAI patients.

Other: Blood samples for the measurement of the concentration of cefazolin; Other: S. aureus culture isolate; Other: structured telephone interview; Other: Sub-study quantitative measurement of Torque Teno virus

Sub-study: cefazolin concentrations in sweat

Out of the study population (patients with CSAI) a total of 15 CSAI patients will be included for the substudy investigating cefazolin concentrations in sweat as a non-invasive therapeutic drug monitoring.

Other: Blood samples for the measurement of the concentration of cefazolin; Other: S. aureus culture isolate; Other: structured telephone interview; Other: Sub-study investigating cefazolin concentrations in sweat

Interventions

Blood samples for the measurement of the concentration of cefazolin OTHER

Blood samples for the measurement of the concentration of cefazolin will be collected on the 1st (mid-dose and trough sample), 3rd (mid-dose and trough sample),7th and 14th day (for both only trough sample) of cefazolin treatment (+/-1-5 day) and if applicable in weekly intervals during outpatient parenteral antibiotic treatment (usually within 4 weeks after inclusion; only in patients on outpatient continuous parenteral antibiotic treatment).

Study population: patients with CSAI caused by MSSA; Sub-study: Torque Teno virus (TTV) viremia; Sub-study: cefazolin concentrations in sweat

S. aureus culture isolate OTHER

The S. aureus culture isolate will be subjected to exact cefazolin MIC determination and to measurement of the level of cefazolin tolerance.

Study population: patients with CSAI caused by MSSA; Sub-study: Torque Teno virus (TTV) viremia; Sub-study: cefazolin concentrations in sweat

structured telephone interview OTHER

Structured telephone interview for Patient follow- up after 30 days

Study population: patients with CSAI caused by MSSA; Sub-study: Torque Teno virus (TTV) viremia; Sub-study: cefazolin concentrations in sweat

Sub-study quantitative measurement of Torque Teno virus OTHER

An additional EDTA sample will be drawn for quantitative polymerase chain reaction (PCR) of TTV DNA and analyses of cytokines and other parameters of the activation state of the immune system.

Sub-study: Torque Teno virus (TTV) viremia

Sub-study investigating cefazolin concentrations in sweat OTHER

For each visit of included patients, a sweat sample will be collected via a CE certified Macroduct Sweat Collector. Eccrine sweat glands of the lower forearms are stimulated by pilocarpine (a parasympathomimetic) as well as a local current for 5min. Sweat is subsequently collected by capillary containers during 30min and transferred to small tubes on dry ice. Sweat sample analysis is conducted using mass spectrometry.

Sub-study: cefazolin concentrations in sweat

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Probability Sample

Study Population

Inpatients with CSAI fulfilling the inclusion criteria and admitted at the University Hospital Basel.

You may qualify if:

• CSAI caused by MSSA. CSAI is defined as MSSA BSI with a positive follow-up blood culture result for MSSA or the presence of a site of infection remote from the primary focus caused by hematogenous seeding (e.g. endocarditis, vertebral osteomyelitis) or extension of the infection beyond the primary focus (e.g. septic thrombophlebitis or abscess); or deep-seated infections caused by MSSA (e.g. osteoarticular infections, deepseated abscesses).
• Current or intended treatment with cefazolin

You may not qualify if:

• Previous enrolment into the current study within 30 days
• Hemodialysis (patients on hemofiltration are eligible)
• Patients who are very likely to stop treatment with cefazolin in the next 48 hours as per treating physician (because of treatment failure, switch to oral medication, palliative care, allergy etc.) or who are very likely to be discharged in the next 48 hours as per treating physician.
• Outpatients
• Women who are pregnant (special pharmacokinetic)
• Not-complicated S. aureus infections: non-bacteremic skin- and soft tissue or small Joint infections without deep-seated abscesses (as these patients will be quickly switched to oral antibiotics)
• CSAI caused by methicillin-resistant S. aureus (MRSA)
• Allergic to pilocarpine
• Continuous oxygen therapy without the possibility to interrupt oxygen administration for 10min
• Pacemaker

Sponsors & Collaborators

• University Hospital, Basel, Switzerland: lead
• propatient foundation Basel: collaborator

Study Sites (1)

University Hospital Basel, Division of Internal Medicine

Basel, 4031, Switzerland

Location

Biospecimen

Retention: SAMPLES WITH DNA

All bacterial isolates from the patients will be stored in the biobank of the microbiology department of the University Hospital Basel.

MeSH Terms

Conditions

Staphylococcal Infections; Sepsis

Interventions

Blood Specimen Collection; Sweating

Condition Hierarchy (Ancestors)

Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Specimen Handling; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Punctures; Surgical Procedures, Operative; Investigative Techniques; Body Temperature Regulation; Body Temperature; Physiological Phenomena; Homeostasis; Skin Physiological Phenomena; Integumentary System Physiological Phenomena; Adaptation, Physiological; Adaptation, Biological; Biological Phenomena

Study Officials

• Michael Osthoff, PD Dr. med.

  University Hospital Basel, Division of Internal Medicine

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 29, 2020
• First Posted: August 7, 2020
• Study Start: January 14, 2020
• Primary Completion: March 28, 2022
• Study Completion: March 28, 2022
• Last Updated: March 29, 2022

Record last verified: 2022-03

Locations

CH (1)