Genomic Insights into and In Vitro Evaluation of Antimicrobial Combination Therapies for Carbapenem-Resistant Acinetobacter baumannii
Abstract
1. Introduction
2. Materials and Methods
2.1. Isolation and Phenotypic Characterization of CRAB
2.2. Molecular Detection of Resistant Genes
2.3. Phylogenetic Analysis of Carbapenemase- and MBL-Encoding Genes of CRAB
2.4. Mutational Analysis of Carbapenemase-Encoding Genes of CRAB
2.5. Combination Synergy Testing
- An FIC index ≤ 0.5 indicates synergy
- An FIC index within 0.5–1 indicates partial synergy
- An FIC index ≥ 1–<4 indicates indifference
- An FIC index ≥ 4 indicates antagonism.
3. Results
3.1. Phenotypic Characterization
3.2. Molecular Characterization of MBL- and Carbapenemase-Encoding Genes of CRAB
3.3. Phylogenetic Studies
3.4. Mutational Analysis of blaOXA Genes of CRAB Isolates
3.5. Synergistic Effects of Antimicrobial Agents
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Sample ID | Source | Specimen | TZP 110 μg | FEP 30 μg | CAZ 30 μg | IPM 10 μg | MEM 10 μg | AK 30 μg | CN 10 μg | TOB 10 μg | DOX 30 μg | CIP 5 μg | LEV 5 μg | SXT 25 ug | CT * | Genes Detected | Genes Sequenced |
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
S-10 | LGH | Tracheal secretions | R | R | R | R | R | R | R | R | S | R | R | R | S | OXA-51, OXA-23, and VIM | OXA-23 and OXA-51 |
S-67 | JHL | Tracheal secretions | R | R | R | R | R | R | R | R | R | R | R | R | S | OXA-24,OXA-23, OXA-51, and VIM | OXA-24 |
S-84 | SHL | Blood | R | R | R | R | R | R | R | R | S | R | R | S | S | OXA-51, OXA-58, and NDM-1 | NDM-1 |
S-96 | SHL | Tracheal secretions | R | R | R | R | R | R | R | R | R | R | R | S | S | OXA-23, OXA-58, OXA-51, and VIM | OXA-58 |
S-97 | CIP | Tracheal secretions | R | R | R | R | R | R | R | R | R | R | R | S | S | OXA-58,OXA-51, and VIM | OXA-58 |
S-98 | CIP | Tissue | R | R | R | R | R | R | R | R | R | R | R | R | S | OXA-23, OXA-58,OXA-51, and VIM | OXA-58 |
Strain | Gene | Mutation | Amino Acid Change | Normal Protein Sequence |
---|---|---|---|---|
S-10 | blaOXA-51 | E11Q | Position 11: Glutamic acid (E) replaced by Glutamine (Q) | TTTEVFKWDGEKRLFPEWEKNMTLGDAMKASAIPVYQDLARRIGLELMSKEVKRVGYGNADIGTQVDNFWLVGPLKITPQQEAQFAYKLANKTLPFSQKVQDEVQS |
K50N | Position 50: Lysine (K) replaced by Asparagine (N) | |||
blaOXA-23 | No mutations | No mutations | No mutations | |
S-67 | blaOXA-24 | M69L | Position 69: Methionine (M) replaced by Leucine (L) | FADDLAHNRLPFKLETQEEVKKMLLIKEVNGSKIYAKSGWGMDVTPQVGWLTGWVEQANGKKIPFSLNM |
S-84 | blaNDM-1 | The mutational analysis was only performed on blaOXA genes | ||
S-96 | blaOXA-58 | I59M | Position 59: Isoleucine (I) replaced by Methionine (M) | TSTIPQVNNSIIDQNVQALFNEISADAVFVTYDGQNIKKYGTHLDRAKTAYIPASTFKIANALIGLENHKATSTEIFKWDGKPRFFKAWDKDFTLGEAMQASTVPVYQELARRIGPSLMQSELQRIGYGNMQIGTEVDQFWLKGPLTITPIQEVKFVYDLAQGQLPFKPEVQQQVKEMLYVERRG |
A60L | Position 60: Alanine (A) replaced by Leucine (L) | |||
P116L | Position 116: Proline (P) replaced by Leucine (L) | |||
S121Q | Position 121: Serine (S) replaced by Glutamine (Q) | |||
F167P | Position 167: Phenylalanine (F) replaced by Proline (P) | |||
S-97 | blaOXA-58 | Q2K | Position 2: Glutamine (Q) replaced by Lysine (K) | EQTGTIPQVNNSIIDQNVQALFNEISADAVFVTYDGQNIKKYGTHLDRAKTAYIPASTFKIANALIGLENHKATSTEIFKWDGKPRFFKAWDKDFTLGEAMQASTVPVYQELARRIGPSLMQSELQRIGYGNMQIGTEVDQFWLKGPLTITPIQEVKFVYDLAQGQLPFKPEVQQQVKEMLYVERRG |
G4S | Position 4: Glycine (G) replaced by Serine (S) | |||
I61M | Position 61: Isoleucine (I) replaced by Methionine (M) | |||
A62L | Position 62: Alanine (A) replaced by Leucine (L) | |||
S-98 | blaOXA-58 | I59M | Position 59: Isoleucine (I) replaced by Methionine (M) | TSTIPQVNNSIIDQNVQALFNEISADAVFVTYDGQNIKKYGTHLDRAKTAYIPASTFKIANALIGLENHKATSTEIFKWDGKPRFFKAWDKDFTLGEAMQASTVPVYQELARRIGPSLMQSELQRIGYGNMQIGTEVDQFWLKGPLTITPIQEVKFVYDLAQGQLPFKPEVQQQVKEMLYV |
Position 60: Alanine (A) replaced by Leucine (L) | ||||
A60L | Position 121: Serine (S) replaced by Lysine (L) | |||
Position 181: Valine (V) replaced by Isoleucine (I) | ||||
S121K | ||||
V181I |
Strain | Gene | Mutation | MUpro | I-MUTANT | PhD SNP | Gene Expression |
---|---|---|---|---|---|---|
S10 | OXA-51 | E11Q | Decrease | Decrease | Neutral | No Change |
K50N | Decrease | Decrease | Neutral | No Change | ||
S96 | OXA-58 | A60L | Decrease | Decrease | Disease | No Change |
I59M | Decrease | Decrease | Disease | No Change | ||
P116L | Increase | Increase | Neutral | Change | ||
S121Q | Decrease | Increase | Neutral | No Change | ||
F167P | Decrease | Decrease | Disease | No Change | ||
S97 | OXA-58 | Q2K | Decrease | Decrease | Neutral | No Change |
G4S | Decrease | Decrease | Neutral | No Change | ||
I61M | Decrease | Decrease | Disease | No Change | ||
A62L | Decrease | Decrease | Disease | No Change | ||
S98 | OXA-58 | A60L | Decrease | Decrease | Disease | No Change |
I59M | Decrease | Decrease | Disease | No Change | ||
S121K | Decrease | Increase | Neutral | No Change | ||
V181I | Increase | Decrease | Neutral | No Change | ||
S67 | OXA-24 | M69L | Increase | Decrease | Neutral | No Change |
Sample ID | Genes Detected | Rifampicin | Colistin | Azithromycin | Meropenem |
---|---|---|---|---|---|
CLSI Breakpoint | R ≥ 4 μg | R ≥ 4 μg | R ≥ 32 μg | R ≥ 8 μg | |
S-10 | OXA-23, OXA-51, and VIM | 128 | 2 | >256 | 64 |
S-67 | OXA-23, OXA-24, OXA-51, and VIM | 128 | 2 | >256 | 64 |
S-84 | OXA-51, OXA-58, and NDM-1 | 128 | 2 | >256 | 64 |
S-96 | VIM, OXA-23, OXA-58, and OXA-51 | 128 | 2 | >256 | 64 |
S-97 | OXA-51, OXA-58, and VIM | 128 | 2 | >256 | 64 |
S-98 | VIM, OXA-58, OXA-51, and OXA-23 | 128 | 2 | >256 | 64 |
Antimicrobial Combinations | Synergy | Partial Synergy | Indifference | Antagonism |
---|---|---|---|---|
FICI Index | ≤0.5 | 0.5–1 | ≥1–<4 | ≥4 |
MEM combined with CT | - | - | S-10, S-67, S-84, S-96, S-97, and S-98 | - |
MEM combined with RIF | - | - | S-10, S-67, S-84, S-96, S-97, and S-98 | - |
MEM combined with AZM | - | - | S-10, S-67, S-84, S-96, S-97, and S-98 | - |
AZM combined with CT | - | - | S-10, S-67, S-84, S-96, S-97, and S-98 | - |
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Ijaz, S.; Ansari, F.; Nawaz, M.; Ejaz, H.; Anjum, A.A.; Saeed, A.; Ali, T.; Rehman, O.U.; Fatima, E.; Ijaz, T. Genomic Insights into and In Vitro Evaluation of Antimicrobial Combination Therapies for Carbapenem-Resistant Acinetobacter baumannii. Medicina 2024, 60, 1086. https://doi.org/10.3390/medicina60071086
Ijaz S, Ansari F, Nawaz M, Ejaz H, Anjum AA, Saeed A, Ali T, Rehman OU, Fatima E, Ijaz T. Genomic Insights into and In Vitro Evaluation of Antimicrobial Combination Therapies for Carbapenem-Resistant Acinetobacter baumannii. Medicina. 2024; 60(7):1086. https://doi.org/10.3390/medicina60071086
Chicago/Turabian StyleIjaz, Saadia, Farheen Ansari, Muhammad Nawaz, Hasan Ejaz, Aftab Ahmad Anjum, Aqib Saeed, Tehreem Ali, Obaid Ur Rehman, Eeshal Fatima, and Tayyaba Ijaz. 2024. "Genomic Insights into and In Vitro Evaluation of Antimicrobial Combination Therapies for Carbapenem-Resistant Acinetobacter baumannii" Medicina 60, no. 7: 1086. https://doi.org/10.3390/medicina60071086
APA StyleIjaz, S., Ansari, F., Nawaz, M., Ejaz, H., Anjum, A. A., Saeed, A., Ali, T., Rehman, O. U., Fatima, E., & Ijaz, T. (2024). Genomic Insights into and In Vitro Evaluation of Antimicrobial Combination Therapies for Carbapenem-Resistant Acinetobacter baumannii. Medicina, 60(7), 1086. https://doi.org/10.3390/medicina60071086