Safety Analysis of Antimicrobial Pharmacotherapy in Intensive Care Unit at Pediatric Hospital

Drug Therapy Clinical Trial

Official title:

Observational Prospective Multidirectional Study on the Safety of Antimicrobial Pharmacotherapy in Intensive Care Unit (ICU) Children Aged 0-17

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04141657
• Other study ID #: 07819001
• Status: Completed
• Start date: February 1, 2020
• Est. completion date: October 15, 2021

Study information

• Verified date: March 2022
• Source: National Medical Research Center for Children's Health, Russian Federation
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

Changes in the metabolic ability of cytochrome P-450 during child development can affect both bioavailability and elimination depending on the involvement of intestinal and hepatic metabolic processes. The age-related variability of cytochrome P-450 isoenzymes in children has been described since 2010. The variability in the development of the activity of specific cytochrome P-450 isoenzymes illustrates why the pharmacogenetic features of the medicine use at different age periods should be studied for individual drugs. This will provide an understanding of the mechanisms for preventing adverse events appearing in pediatric intensive care units while more common antimicrobial pharmacotherapy is administered. Improved knowledge of the pharmacogenetic characteristics of cytochrome P-450 and the unintended consequences of modulation of its isoenzymes could provide an understanding of the susceptibility to adverse events in children in critical conditions staying at Intensive Care unit (ICU).

Description:

An observational prospective multidirectional study on the safety of antimicrobial pharmacotherapy in ICU children aged 0-17. The endpoints of the safety assessment are the frequency of adverse events with antimicrobial agents (AMA); electrocardiography (ECG), fibrinogen concentration, international normalized ratio (INR) and prothrombin index (IPT) at screening and at the end of the treatment course, and pharmacogenetic indicators (a more detailed study of the safety profile). A demonstration of the effectiveness of each of these comparisons of inequality will be based on the hypothesis testing approach, according to which the null hypothesis concludes that there is no difference between groups receiving different AMA combinations for the endpoint of interest; and an alternative hypothesis supposes a difference between treatment groups receiving different AMA combinations. Changes in the sequential organ failure assessment (SOFA) scale in dynamics compared to the baseline will be analyzed using the Mixed-Effect Model Repeated Measure (MMRM) model which assume the baseline, gender, age, AMA combination, and the duration of the AMA course. For a population of subjects aged 0-3 months, the analysis will be performed using the analysis of covariance (ANCOVA) model with the effects of INR, fibrinogen, and IPT values at the initial level for gender, age, and AMA combination in the treatment groups.

To assess the secondary endpoint for the general population - the frequency and timing of the transition to de-escalation at ICU, cluster analysis will be conducted to identify the relationship of specific AMA combinations with the possibility of de-escalation in ICU children.

Studies will be conducted to reveal the relationship in gene polymorphism encoding isoenzymes of the cytochrome P-450 biotransformation, and the relationship between the activity of transport proteins with the indicators of effectiveness and safety of antimicrobial pharmacotherapy. The lack of pharmacological safety studies in children administered medicine combinations to overcome pan-resistant gram-negative infection provides relevant prerequisites for this study.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 100
• Est. completion date: October 15, 2021
• Est. primary completion date: August 28, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A to 17 Years

Eligibility

Inclusion Criteria:

1. Intensive Care Unit (ICU) patient;

2. Community-acquired infections with risk factors for multidrug-resistant pathogens (risk factors for extended-spectrum ß-lactamase (ESBL) - type II;

3. Nosocomial infections - type III:

• IIIa: hospitalized during the period of 90 days, without prior antimicrobial agent (AMA) therapy outside the ICU (risk factors for ESBL);

• IIIb: prolonged hospitalization (> 7 days) and/or stay at ICU for more than 3 days and/or previous AMA therapy (risk factors for ESBL, carbenicillin-resistant (CARB-R), nonfermenting Gram-negative bacteria (NFGNB), methicillin-resistant Staphylococcus aureus (MRSA));

4. Nosocomial infections with a risk of invasive candidiasis - type IV (candida score =2 points);

5. Written informed consent for medical intervention signed by at least one parent or caregiver (legal guardian) or informed consent of a patient under 15 years of age;

6. Written informed consent for pharmacogenetic research signed by at least one parent or caregiver (legal guardian) or informed consent of a patient under 15 years of age.

Exclusion Criteria:

1. Type I: patients with community-acquired infections and without risk factors for multidrug-resistant pathogens, without hospitalization during the previous 90 days;

2. Previous/concomitant therapy is not significant;

3. Children in the ward: children under guardianship are not eligible.

Related Conditions & MeSH terms

• Drug Therapy

Intervention

Other:
• Pharmacogenetic test
Buccal swabs are a relatively non-invasive way to collect deoxyribonucleic acid (DNA) samples for testing. A buccal swab will be performed to collect DNA from the cells on the inside of a subject's cheek for phenotyping of CYP3A4.

Locations

Country	Name	City	State
Russian Federation	Morozov Children's City Clinical Hospital	Moscow

Sponsors (3)

Lead Sponsor	Collaborator
Anna Vlasova	Morozov Children's Municipal Clinical Hospital of the Moscow City Health Department State-Financed, Russian Medical Academy of Continuous Professional Education

Country where clinical trial is conducted

Russian Federation, 

References & Publications (20)

Baietto L, Corcione S, Pacini G, Perri GD, D'Avolio A, De Rosa FG. A 30-years review on pharmacokinetics of antibiotics: is the right time for pharmacogenetics? Curr Drug Metab. 2014;15(6):581-98. Review. — View Citation

Ball P. Quinolone-induced QT interval prolongation: a not-so-unexpected class effect. J Antimicrob Chemother. 2000 May;45(5):557-9. — View Citation

Cui L, Kasegawa H, Murakami Y, Hanaki H, Hiramatsu K. Postoperative toxic shock syndrome caused by a highly virulent methicillin-resistant Staphylococcus aureus strain. Scand J Infect Dis. 1999;31(2):208-9. — View Citation

Ellis-Grosse EJ, Babinchak T, Dartois N, Rose G, Loh E; Tigecycline 300 cSSSI Study Group; Tigecycline 305 cSSSI Study Group. The efficacy and safety of tigecycline in the treatment of skin and skin-structure infections: results of 2 double-blind phase 3 — View Citation

Karadeniz C, Oguz A, Canter B, Serdaroglu A. Incidence of seizures in pediatric cancer patients treated with imipenem/cilastatin. Pediatr Hematol Oncol. 2000 Oct-Nov;17(7):585-90. — View Citation

Kim K, Johnson JA, Derendorf H. Differences in drug pharmacokinetics between East Asians and Caucasians and the role of genetic polymorphisms. J Clin Pharmacol. 2004 Oct;44(10):1083-105. Review. — View Citation

Laughon MM, Avant D, Tripathi N, Hornik CP, Cohen-Wolkowiez M, Clark RH, Smith PB, Rodriguez W. Drug labeling and exposure in neonates. JAMA Pediatr. 2014 Feb;168(2):130-6. doi: 10.1001/jamapediatrics.2013.4208. — View Citation

León C, Ruiz-Santana S, Saavedra P, Almirante B, Nolla-Salas J, Alvarez-Lerma F, Garnacho-Montero J, León MA; EPCAN Study Group. A bedside scoring system ("Candida score") for early antifungal treatment in nonneutropenic critically ill patients with Candi — View Citation

Martinez Tadeo JA, Perez Rodriguez E, Almeida Sanchez Z, Callero Viera A, Garcia Robaina JC. No Cross-Reactivity With Cephalosporins in Patients With Penicillin Allergy. J Investig Allergol Clin Immunol. 2015;25(3):216-7. — View Citation

Matthews HW. Racial, ethnic and gender differences in response to medicines. Drug Metabol Drug Interact. 1995;12(2):77-91. Review. — View Citation

McGovern PC, Wible M, El-Tahtawy A, Biswas P, Meyer RD. All-cause mortality imbalance in the tigecycline phase 3 and 4 clinical trials. Int J Antimicrob Agents. 2013 May;41(5):463-7. doi: 10.1016/j.ijantimicag.2013.01.020. Epub 2013 Mar 26. — View Citation

Norrby SR. Carbapenems in serious infections: a risk-benefit assessment. Drug Saf. 2000 Mar;22(3):191-4. Review. — View Citation

Odio CM, Puig JR, Feris JM, Khan WN, Rodriguez WJ, McCracken GH Jr, Bradley JS. Prospective, randomized, investigator-blinded study of the efficacy and safety of meropenem vs. cefotaxime therapy in bacterial meningitis in children. Meropenem Meningitis St — View Citation

Prot-Labarthe S, Weil T, Angoulvant F, Boulkedid R, Alberti C, Bourdon O. POPI (Pediatrics: Omission of Prescriptions and Inappropriate prescriptions): development of a tool to identify inappropriate prescribing. PLoS One. 2014 Jun 30;9(6):e101171. doi: 1 — View Citation

Schliamser SE, Broholm KA, Liljedahl AL, Norrby SR. Comparative neurotoxicity of benzylpenicillin, imipenem/cilastatin and FCE 22101, a new injectible penem. J Antimicrob Chemother. 1988 Nov;22(5):687-95. — View Citation

Setiawan E, Suwannoi L, Montakantikul P, Chindavijak B. Optimization of Intermittent Vancomycin Dosage Regimens for Thai Critically Ill Population Infected by MRSA in the Era of the "MIC Creep" Phenomenon. Acta Med Indones. 2019 Jan;51(1):10-18. — View Citation

Smith RG. Penicillin and cephalosporin drug allergies: a paradigm shift. J Am Podiatr Med Assoc. 2008 Nov-Dec;98(6):479-88. Review. — View Citation

Ward RM, Benjamin D, Barrett JS, Allegaert K, Portman R, Davis JM, Turner MA. Safety, dosing, and pharmaceutical quality for studies that evaluate medicinal products (including biological products) in neonates. Pediatr Res. 2017 May;81(5):692-711. doi: 10 — View Citation

Winston DJ, Lazarus HM, Beveridge RA, Hathorn JW, Gucalp R, Ramphal R, Chow AW, Ho WG, Horn R, Feld R, Louie TJ, Territo MC, Blumer JL, Tack KJ. Randomized, double-blind, multicenter trial comparing clinafloxacin with imipenem as empirical monotherapy for — View Citation

Yahav D, Lador A, Paul M, Leibovici L. Efficacy and safety of tigecycline: a systematic review and meta-analysis. J Antimicrob Chemother. 2011 Sep;66(9):1963-71. doi: 10.1093/jac/dkr242. Epub 2011 Jun 18. Review. — View Citation

* Note: There are 20 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Adverse events frequency	Registered adverse events in participants during the treatment course	From baseline until the date of first documented progression, assessed up to 1 month
Primary	ECG QT Interval change	Assessment of QT Interval change at the end of the AMA course comparing with screening measurement	Change from screening QT Interval at 1 month

External Links

•   Daniel CR, Frey OR, Roehr A, et al. Therapeutic drug monitoring (TDM)-guided continuous infusion (CI) of piperacillin/tazobactam (PIP) reduces the mortality of critically ill patients in the intensive care unit (ICU). ECCMID Conference, 2019.
•   Guideline on the Investigation of Medicinal Products in the Term and Preterm Neonate. London, UK: European Medicines Agency; 2009.
•   Karaiskos I, Barmpouti E, Ioannidis K, et al. Hypofibrinogenaemia associated with the administration of tigecycline. Conference Paper (poster). Conference: 24th ECCMID; 2014, Barcelona, Spain. doi: 10.13140/2.1.2337.2163.
•   Kees F, Kratzer A, et al. In vitro investigations on the atypical protein binding behaviour of tigecycline using ultrafiltration. ECCMID; April 27 2015, Copenhagen, Denmark. Paper Poster Session V: Pharmacokinetics in various patient groups. P 1137.