Synergy Between Plasmid Inhibitors and Combined AntibioticsNCT05932355
Synergistic Effect of Plasmid Inhibitors and Antimicrobial Drugs Against Clinical MDR-hvKP
An observational study of Synergy Between Plasmid Inhibitors and Combined Antibiotics, run by Assiut University.
Trial summary
1. Screening for MDR-hvKP causing VAP in patients admitted to chest ICU in Assiut University Hospital. 2. In vitro evaluation of the synergistic activity of combined meropenem/levofloxacin with and without kasugamycin against clinical MDR-hvKP isolates by checkerboard and time killing assay. 3. Read more about this study
- Who is it for?
- Any age
- Conditions the study is for
- Synergy Between Plasmid Inhibitors and Combined Antibiotics
- How many people
- 50 participants
- Where
- No sites listed yet
- Study dates
- Jul 2023to Aug 2025
- Phase
- Observational
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages Any age
- All sexes
- Child, Adult, Older adult
Study population: Fifty VAP patients with no other chest diseases will be included in the study.
Who may be able to join
- VAP patients (patients under mechanical ventilation for more than 48 h with new or progressive infiltrate on chest X-ray and have at least two of the following criteria:
- Fever (>38 oC) with no other recognized cause
- WBCs < 4000/mm3 or >12000/mm3
- New onset of purulent sputum.
- Increase in respiratory secretion or increased need for suctioning.
- New-onset or worsening cough, or dyspnea, or tachypnea worsening gas exchange.
Who cannot join
- Patients with chest diseases other than VAP .
Trial locations and contacts
No sites are listed yet.
About this study
Official title: Assessment of the Effect of Plasmid Inhibitors and Antimicrobial Drugs as Combined Strategy Against Clinical Multi-drug Resistant Hypervirulent Klebsiella Pneumoniae
- Screening for MDR-hvKP causing VAP in patients admitted to chest ICU in Assiut University Hospital.
- In vitro evaluation of the synergistic activity of combined meropenem/levofloxacin with and without kasugamycin against clinical MDR-hvKP isolates by checkerboard and time killing assay.
- In vivo evaluation of the synergistic activity of combined meropenem/levofloxacin with and without kasugamycin using MDR-hvKP septic rat model.
Read the detailed description
New "hypervirulent" Klebsiella-pneumoniae (hvKp) strain has emerged as a clinically-significant-pathogen in both healthy and immunocompromised individuals . HvKp, at its discovery, was rarely resistant to antimicrobial-agents , however, nowadays, antibiotic-resistant hvKP isolates are being reported .
Plasmids are important vectors that bacteria use to transfer resistance and virulence determinants. Typically, genetic elements conferring resistance and virulence were encoded by different plasmids . Most recently, clinicians have been faced, the confluence of resistance and virulence-determinants on the same or coexisting-plasmids with the evolution of multidrug-resistant (MDR) and hypervirulent Klebsiella pneumoniae hvKP .
One approach to combat MDR infections is to combine antimicrobial drugs during a treatment-regimen . Fluoroquinolone plus carbapenems is one of-the most useful-combination used in cases which suffer from MDR to most available monotherapies . Another-approach is Plasmid curing, using plasmid inhibitors, which is the method of removing plasmids from the bacterial populations while leaving the population intact leading to reversal of the plasmid-mediated antibiotic resistance .
Kasugamycin, an-aminoglycoside; is a compound exhibiting significant-antiplasmid activity-up-to-complete suppression of plasmid-replication . Kasugamycin was found to block plasmid replication by inhibiting-expression of plasmid replication initiation-protein, RepE, and to reduce plasmid-levels by 90% . Accordingly, we hypothesize that, using dual-antibiotics supplemented with plasmid inhibitor will be efficient in inhibiting MDR-hvKP, both in vitro and in vivo.
This is the first-study to evaluate the effect of addition of plasmid inhibitor on improving the efficacy of antibiotics and improve their synergistic activity. The results of this study will open the door for-using plasmid-inhibitor-compounds on restoring the usefulness of many conventional-antibiotics to which-resistance has emerged.
What is being measured
The primary outcome is the main question the study is designed to answer.
Synergistic effect of plasmid inhibitors and antimicrobial drugs against MDR-hvKP invitro.
Assessment of synergy invitro by :
Checkerboard assay : Fractional inhibitory concentrations index (FICI) will be calculated as:
FICI = FIC A (MIC for antibiotic A in combination) / (MIC antibiotic A) + FIC B (MIC antibiotic B in combination) / (MIC antibiotic B). (It is a ratio)
Synergy is defined as FICI ≤0.5, no interaction is defined as FICI > 0.5 and ≤ 4, and antagonism is defined as FICI >4 .
.
Measured: 24hours
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted6 Jul 2023
- Study startJul 2023 (estimated)
- Primary completionJul 2025 (estimated)
- Study completionAug 2025 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (8)Papers the sponsor has linked to this study.
- Other trials for Synergy Between Plasmid Inhibitors and Combined AntibioticsStudies of the same condition, open and under way.
- More trials run by Assiut UniversityThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Cohort
- Time perspective
- Prospective
- Enrolment
- 50 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Assiut University
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Shereen Elnokrashy Mohamed, Assiut University
- Investigators
- Sherine Aly, Professor, Study director, Department of Microbiology and ImmunologyWegdan Mohamad, Assistant Professor, Study director, Department of Microbiology and Immunology
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05932355
- Sponsor's protocol ID
- Plasmid inhibitors in MDR-hvKP
- Status last verified
- Jun 2023
- First submitted
- 15 May 2023
- Last updated
- 6 Jul 2023
- Results posted
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
Publications
Prokesch BC, TeKippe M, Kim J, Raj P, TeKippe EM, Greenberg DE. Primary osteomyelitis caused by hypervirulent Klebsiella pneumoniae. Lancet Infect Dis. 2016 Sep;16(9):e190-e195. doi: 10.1016/S1473-3099(16)30021-4. Epub 2016 Jul 9.
PubMed 27402393Zhang Y, Zhao C, Wang Q, Wang X, Chen H, Li H, Zhang F, Li S, Wang R, Wang H. High Prevalence of Hypervirulent Klebsiella pneumoniae Infection in China: Geographic Distribution, Clinical Characteristics, and Antimicrobial Resistance. Antimicrob Agents Chemother. 2016 Sep 23;60(10):6115-20. doi: 10.1128/AAC.01127-16. Print 2016 Oct.
PubMed 27480857Zhan L, Wang S, Guo Y, Jin Y, Duan J, Hao Z, Lv J, Qi X, Hu L, Chen L, Kreiswirth BN, Zhang R, Pan J, Wang L, Yu F. Outbreak by Hypermucoviscous Klebsiella pneumoniae ST11 Isolates with Carbapenem Resistance in a Tertiary Hospital in China. Front Cell Infect Microbiol. 2017 May 16;7:182. doi: 10.3389/fcimb.2017.00182. eCollection 2017.
PubMed 28560183Feng Y, Lu Y, Yao Z, Zong Z. Carbapenem-Resistant Hypervirulent Klebsiella pneumoniae of Sequence Type 36. Antimicrob Agents Chemother. 2018 Jun 26;62(7):e02644-17. doi: 10.1128/AAC.02644-17. Print 2018 Jul.
PubMed 29712659Worthington RJ, Melander C. Combination approaches to combat multidrug-resistant bacteria. Trends Biotechnol. 2013 Mar;31(3):177-84. doi: 10.1016/j.tibtech.2012.12.006. Epub 2013 Jan 18.
PubMed 23333434Drago L, De Vecchi E, Nicola L, Colombo A, Guerra A, Gismondo MR. Activity of levofloxacin and ciprofloxacin in combination with cefepime, ceftazidime, imipenem, piperacillin-tazobactam and amikacin against different Pseudomonas aeruginosa phenotypes and Acinetobacter spp. Chemotherapy. 2004 Oct;50(4):202-10. doi: 10.1159/000081033. Epub 2004 Sep 23.
PubMed 15452399Vrancianu CO, Popa LI, Bleotu C, Chifiriuc MC. Targeting Plasmids to Limit Acquisition and Transmission of Antimicrobial Resistance. Front Microbiol. 2020 May 6;11:761. doi: 10.3389/fmicb.2020.00761. eCollection 2020.
PubMed 32435238Zulauf KE, Kirby JE. Discovery of small-molecule inhibitors of multidrug-resistance plasmid maintenance using a high-throughput screening approach. Proc Natl Acad Sci U S A. 2020 Nov 24;117(47):29839-29850. doi: 10.1073/pnas.2005948117. Epub 2020 Nov 9.
PubMed 33168749
Study at a glance
From the registry record, last updated by the sponsor on 6 Jul 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Assessment of the Effect of Plasmid Inhibitors and Antimicrobial Drugs as Combined Strategy Against Clinical Multi-drug Resistant Hypervirulent Klebsiella Pneumoniae
- ClinicalTrials.gov ID
- NCT05932355
- Acronym / sponsor ID
- Plasmid inhibitors in MDR-hvKP
- Study type
- Observational
- Recruitment status
- Unknown status
- Enrolment
- 50 participants (estimated)
- Lead sponsor
- Assiut UniversityUniversity, hospital or other
- Study start
- Jul 2023 (estimated)
- Primary completion
- Jul 2025 (estimated)
- Study completion
- Aug 2025 (estimated)
- First posted
- 6 Jul 2023 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
- Screening for MDR-hvKP causing VAP in patients admitted to chest ICU in Assiut University Hospital.
- In vitro evaluation of the synergistic activity of combined meropenem/levofloxacin with and without kasugamycin against clinical MDR-hvKP isolates by checkerboard and time killing assay.
- In vivo evaluation of the synergistic activity of combined meropenem/levofloxacin with and without kasugamycin using MDR-hvKP septic rat model.
Detailed description
New "hypervirulent" Klebsiella-pneumoniae (hvKp) strain has emerged as a clinically-significant-pathogen in both healthy and immunocompromised individuals . HvKp, at its discovery, was rarely resistant to antimicrobial-agents , however, nowadays, antibiotic-resistant hvKP isolates are being reported .
Plasmids are important vectors that bacteria use to transfer resistance and virulence determinants. Typically, genetic elements conferring resistance and virulence were encoded by different plasmids . Most recently, clinicians have been faced, the confluence of resistance and virulence-determinants on the same or coexisting-plasmids with the evolution of multidrug-resistant (MDR) and hypervirulent Klebsiella pneumoniae hvKP .
One approach to combat MDR infections is to combine antimicrobial drugs during a treatment-regimen . Fluoroquinolone plus carbapenems is one of-the most useful-combination used in cases which suffer from MDR to most available monotherapies . Another-approach is Plasmid curing, using plasmid inhibitors, which is the method of removing plasmids from the bacterial populations while leaving the population intact leading to reversal of the plasmid-mediated antibiotic resistance .
Kasugamycin, an-aminoglycoside; is a compound exhibiting significant-antiplasmid activity-up-to-complete suppression of plasmid-replication . Kasugamycin was found to block plasmid replication by inhibiting-expression of plasmid replication initiation-protein, RepE, and to reduce plasmid-levels by 90% . Accordingly, we hypothesize that, using dual-antibiotics supplemented with plasmid inhibitor will be efficient in inhibiting MDR-hvKP, both in vitro and in vivo.
This is the first-study to evaluate the effect of addition of plasmid inhibitor on improving the efficacy of antibiotics and improve their synergistic activity. The results of this study will open the door for-using plasmid-inhibitor-compounds on restoring the usefulness of many conventional-antibiotics to which-resistance has emerged.
Study design
- Observational model
- Cohort
- Time perspective
- Prospective
Who may qualify
- Sex
- All
- Age groups
- Child, Adult, Older adult
- Study population
- Fifty VAP patients with no other chest diseases will be included in the study.
Key inclusion criteria (6 listed)
- VAP patients (patients under mechanical ventilation for more than 48 h with new or progressive infiltrate on chest X-ray and have at least two of the following criteria:
- Fever (>38 oC) with no other recognized cause
- WBCs < 4000/mm3 or >12000/mm3
- New onset of purulent sputum.
- Increase in respiratory secretion or increased need for suctioning.
Key exclusion criteria (1 listed)
- Patients with chest diseases other than VAP .
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Primary outcome
Synergistic effect of plasmid inhibitors and antimicrobial drugs against MDR-hvKP invitro.
Time frame: 24hours
Assessment of synergy invitro by : Checkerboard assay : Fractional inhibitory concentrations index (FICI) will be calculated as: FICI = FIC A (MIC for antibiotic A in combination) / (MIC antibiotic A) + FIC B (MIC antibiotic B in combination) / (MIC antibiotic B). (It is a ratio) Synergy is defined as FICI ≤0.5, no interaction is defined as FICI > 0.5 and ≤ 4, and antagonism is defined as FICI >4 . .
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 6 Jul 2023.
- Background: PubMed 27402393Prokesch BC, TeKippe M, Kim J, Raj P, TeKippe EM, Greenberg DE. Primary osteomyelitis caused by hypervirulent Klebsiella pneumoniae. Lancet Infect Dis. 2016 Sep;16(9):e190-e195. doi: 10.1016/S1473-3099(16)30021-4. Epub 2016 Jul 9.
- Background: PubMed 27480857Zhang Y, Zhao C, Wang Q, Wang X, Chen H, Li H, Zhang F, Li S, Wang R, Wang H. High Prevalence of Hypervirulent Klebsiella pneumoniae Infection in China: Geographic Distribution, Clinical Characteristics, and Antimicrobial Resistance. Antimicrob Agents Chemother. 2016 Sep 23;60(10):6115-20. doi: 10.1128/AAC.01127-16. Print 2016 Oct.
- Background: PubMed 28560183Zhan L, Wang S, Guo Y, Jin Y, Duan J, Hao Z, Lv J, Qi X, Hu L, Chen L, Kreiswirth BN, Zhang R, Pan J, Wang L, Yu F. Outbreak by Hypermucoviscous Klebsiella pneumoniae ST11 Isolates with Carbapenem Resistance in a Tertiary Hospital in China. Front Cell Infect Microbiol. 2017 May 16;7:182. doi: 10.3389/fcimb.2017.00182. eCollection 2017.
- Background: PubMed 29712659Feng Y, Lu Y, Yao Z, Zong Z. Carbapenem-Resistant Hypervirulent Klebsiella pneumoniae of Sequence Type 36. Antimicrob Agents Chemother. 2018 Jun 26;62(7):e02644-17. doi: 10.1128/AAC.02644-17. Print 2018 Jul.
- Background: PubMed 23333434Worthington RJ, Melander C. Combination approaches to combat multidrug-resistant bacteria. Trends Biotechnol. 2013 Mar;31(3):177-84. doi: 10.1016/j.tibtech.2012.12.006. Epub 2013 Jan 18.
- Background: PubMed 15452399Drago L, De Vecchi E, Nicola L, Colombo A, Guerra A, Gismondo MR. Activity of levofloxacin and ciprofloxacin in combination with cefepime, ceftazidime, imipenem, piperacillin-tazobactam and amikacin against different Pseudomonas aeruginosa phenotypes and Acinetobacter spp. Chemotherapy. 2004 Oct;50(4):202-10. doi: 10.1159/000081033. Epub 2004 Sep 23.
- Background: PubMed 32435238Vrancianu CO, Popa LI, Bleotu C, Chifiriuc MC. Targeting Plasmids to Limit Acquisition and Transmission of Antimicrobial Resistance. Front Microbiol. 2020 May 6;11:761. doi: 10.3389/fmicb.2020.00761. eCollection 2020.
- Background: PubMed 33168749Zulauf KE, Kirby JE. Discovery of small-molecule inhibitors of multidrug-resistance plasmid maintenance using a high-throughput screening approach. Proc Natl Acad Sci U S A. 2020 Nov 24;117(47):29839-29850. doi: 10.1073/pnas.2005948117. Epub 2020 Nov 9.
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Sherine Aly, Professor study director
Department of Microbiology and Immunology
Wegdan Mohamad, Assistant Professor study director
Department of Microbiology and Immunology
Questions about this trial
What is this clinical trial studying?
An observational study of Synergy Between Plasmid Inhibitors and Combined Antibiotics, run by Assiut University.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 6 inclusion and 1 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 6 Jul 2023. Status can change between updates, so confirm with the study contact before making plans.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Shereen Elnokrashy Mohamed, Teaching Assistant (+201093156381, shereenelnokrashy96@gmail.com), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Synergistic effect of plasmid inhibitors and antimicrobial drugs against MDR-hvKP invitro. (time frame: 24hours). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT05932355, which also lists 8 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 6 Jul 2023.