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  1. Fulltext Carbapenem resistance gene crisis in A. baumannii: a computational analysis
    Zahra N, Zeshan B, Ishaq M
    BMC Microbiol, 2022 Dec 03;22(1):290.
    PMID: 36463105 DOI: 10.1186/s12866-022-02706-8
    Acinetobacter baumannii (A. baumannii) is one of the members of ESKAPE bacteria which is considered multidrug resistant globally. The objective of this study is to determine the protein docking of different antibiotic resistance gene (ARGs) in A. baumannii. In silico analysis of antibiotic resistance genes against carbapenem are the blaOXA-51, blaOXA-23, blaOXA-58, blaOXA-24, blaOXA-143, NMD-1 and IMP-1 in A. baumannii. The doripenem, imipenem and meropenem were docked to blaOXA-51 and blaOXA-23 using PyRx. The top docking energy was -5.5 kcal/mol by imipenem and doripenem and meropenem showed a binding score of -5. 2 kcal/mol each and blaOXA-23 energy was -4.3 kcal/mol by imipenem and meropenem showed a binding score of -2.3 kcal/mol, while doripenem showed the binding score of -3.4 kcal/mol. Similarly, doripenem imipenem and meropenem were docked to blaOXA-58, IMP-1, Rec A and blaOXA-143, with docking energy was -8.8 kcal/mol by doripenem and meropenem each while imipenem showed a binding score of -4.2 kcal/mol and with IMP-1 demonstrated their binding energies. was -5.7 kcal/mol by meropenem and doripenem showed a binding score of -5.3 kcal/mol, while imipenem showed a binding score of -4.5 kcal/mol. And docking energy was -4.9 kcal/mol by imipenem and meropenem showed binding energy of -3.6 kcal/mol each while doripenem showed a binding score of -3.9 kcal/mol in RecA and with blaOXA-143 docking energy was -3.0 kcal/mol by imipenem and meropenem showed a binding score of -1.9 kcal/mol, while doripenem showed the binding score of -2.5 kcal/mol respectively. Doripenem, imipenem, and meropenem docking findings with blaOXA-24 confirmed their binding energies. Doripenem had the highest docking energy of -5.5 kcal/mol, meropenem had a binding score of -4.0 kcal/mol, and imipenem had a binding score of -3.9 kcal/mol. PyRx was used to dock the doripenem, imipenem, and meropenem to NMD-1. Docking energies for doripenem were all - 4.0 kcal/mol, whereas meropenem had docking energy of -3.3 kcal/mol and imipenem was -1.50 kcal/mol. To the best of our knowledge the underlying mechanism of phenotypic with genotypic resistance molecular docking regarding carbapenem resistance A. baumannii is unclear. Our molecular docking finds the possible protein targeting mechanism for carbapenem-resistant A.baumannii.
    Matched MeSH terms: Imipenem/pharmacology
  2. Computational modelling of potential Zn-sensitive non-β-lactam inhibitors of imipenemase-1 (IMP-1)
    Ayipo YO, Ahmad I, Alananzeh W, Lawal A, Patel H, Mordi MN
    J Biomol Struct Dyn, 2023 Nov;41(19):10096-10116.
    PMID: 36476097 DOI: 10.1080/07391102.2022.2153168
    Antibiotic resistance (AR) remains one of the leading global health challenges, mostly implicated in disease-related deaths. The Enterobacteriaceae-producing metallo-β-lactamases (MBLs) are critically involved in AR pathogenesis through Zn-dependent catalytic destruction of β-lactam antibiotics, yet with limited successful clinical inhibitors. The efficacy of relevant broad-spectrum β-lactams including imipenem and meropenem are seriously challenged by their susceptibility to the Zn-dependent carbapenemase hydrolysis, as such, searching for alternatives remains imperative. In this study, computational molecular modelling and virtual screening methods were extensively applied to identify new putative Zn-sensitive broad-spectrum inhibitors of MBLs, specifically imipenemase-1 (IMP-1) from the IBScreen database. Three ligands, STOCK3S-30154, STOCK3S-30418 and STOCK3S-30514 selectively displayed stronger binding interactions with the enzymes compared to reference inhibitors, imipenem and meropenem. For instance, the ligands showed molecular docking scores of -9.450, -8.005 and -10.159 kcal/mol, and MM-GBSA values of -40.404, -31.902 and -33.680 kcal/mol respectively against the IMP-1. Whereas, imipenem and meropenem showed docking scores of -9.038 and -10.875 kcal/mol, and MM-GBSA of -31.184 and -32.330 kcal/mol respectively against the enzyme. The ligands demonstrated good thermodynamic stability and compactness in complexes with IMP-1 throughout the 100 ns molecular dynamics (MD) trajectories. Interestingly, their binding affinities and stabilities were significantly affected in contacts with the remodelled Zn-deficient IMP-1, indicating sensitivity to the carbapenemase active Zn site, however, with non-β-lactam scaffolds, tenable to resist catalytic hydrolysis. They displayed ideal drug-like ADMET properties, thus, representing putative Zn-sensitive non-β-lactam inhibitors of IMP-1 amenable for further experimental studies.
    Matched MeSH terms: Imipenem/pharmacology
  3. Distribution of extended spectrum beta-lactamase resistance genes among nosocomial imipenem resistant A. Baumannii strains harboring BLAoxa-23 carbapenemases isolated from Ilam and Tehran
    Taherikalani M, Sekawi Z, Azizi-Jalilian F, Keshavarz B, Soroush S, Akbari M, et al.
    J Biol Regul Homeost Agents, 2013 Jul-Sep;27(3):883-9.
    PMID: 24152853
    Antimicrobial susceptibility and ESBLs genes of 42 imipenem resistant A. baumannii carried out by DDST and PCR. The most antimicrobial agents against A. baumannii strains, harboring blaOXA-23-like carbapenemases, were meropenem (33.4 percent), piperacillin-tazobactam (23.9 percent), ceftazidime (14.3 percent) and gatifoxacin (19.1 percent), respectively. All the 42 isolates harbored the blaTEM gene, but the bla SHV and VEB genes were not present among all the isolates. With the exception of seven isolates, all the A. baumannii strains harbor blaTEM showed ESBL positivity in DDST. The result of this study show that resistance against antimicrobial agents, especially carbapenems, has increased and that blaTEM harboring A. baumannii strains can be help the blaOXA-like carbapenemase genes to code for resistance against carbapenem antibiotics.
    Matched MeSH terms: Imipenem/pharmacology*
  4. Fulltext Phenotypic detection of metallo-β-lactamase in imipenem-resistant Pseudomonas aeruginosa
    Khosravi Y, Loke MF, Chua EG, Tay ST, Vadivelu J
    ScientificWorldJournal, 2012;2012:654939.
    PMID: 22792048 DOI: 10.1100/2012/654939
    Carbapenems are the primary choice of treatment for severe Pseudomonas aeruginosa infection. However, the emergence of carbapenem resistance due to the production of metallo-β-lactamases (MBLs) is of global concern. In this study, 90 imipenem- (IPM- or IP-) resistant P. aeruginosa (IRPA) isolates, including 32 previously tested positive and genotyped for MBL genes by PCR, were subjected to double-disk synergy test (DDST), combined disk test (CDT), and imipenem/imipenem-inhibitor (IP/IPI) E-test to evaluate their MBLs detection capability. All three methods were shown to have a sensitivity of 100%. However, DDST was the most specific of the three (96.6%), followed by IP/IPI E-test interpreted based on the single criteria of IP/IPI ≥8 as positive (62.1%), and CDT was the least specific (43.1%). Based on the data from this evaluation, we propose that only IRPA with IP MIC >16 μg/mL and IP/IPI ≥8 by IP/IPI E-test should be taken as positive for MBL activity. With the new dual interpretation criteria, the MBL IP/IPI E-test was shown to achieve 100% sensitivity as well as specificity for the IRPA in this study. Therefore, the IP/IPI E-test is a viable alternative phenotypic assay to detect MBL production in IRPA in our population in circumstances where PCR detection is not a feasible option.
    Matched MeSH terms: Imipenem/pharmacology*
  5. Burkholderia pseudomallei: in vitro susceptibility to some new and old antimicrobials
    Karunakaran R, Puthucheary SD
    Scand. J. Infect. Dis., 2007;39(10):858-61.
    PMID: 17852912
    The treatment of melioidosis currently involves the use of antimicrobials such as ceftazidime, trimethoprim-sulfamethoxazole, amoxicillin-clavulanate and doxycycline. Evaluation of other antimicrobials with activity against the organism continues to be pursued, however, as the causative organism, B. pseudomallei, may not always be susceptible to the above antimicrobials. This study aimed to test the susceptibility of Malaysian isolates of B. pseudomallei against imipenem, meropenem, ertapenem, moxifloxacin and azithromycin. 80 previously stocked clinical isolates collected between 1978 and 2003 from the UMMC, Kuala Lumpur were tested for in vitro susceptibility to these antimicrobials using the E-test minimum inhibitory concentration method. 100% of isolates were sensitive to imipenem and meropenem, 97.5% were sensitive to trimethoprim-sulfamethozaxole, 37.5% to moxifloxacin, and only a minority was sensitive to ertapenem (7.5%). Using breakpoints for Staphylococcus and Haemophilus, 5.0%-6.3% of isolates were sensitive to azithromycin. In conclusion, our findings support the in vitro efficacy of imipenem, meropenem and trimethoprim-sulfamethoxazole against B. pseudomallei. Moxifloxacin, ertapenem and azithromycin cannot be recommended for the treatment of melioidosis; however, further studies are needed to test the efficacy of azithromycin in combination with quinolones.
    Matched MeSH terms: Imipenem/pharmacology*
  6. Interaction of LysM BON family protein domain with carbapenems: A putative mechanism of carbapenem resistance
    Ali A, Kumar R, Khan A, Khan AU
    Int J Biol Macromol, 2020 Oct 01;160:212-223.
    PMID: 32464197 DOI: 10.1016/j.ijbiomac.2020.05.172
    Carbapenem resistance in Gram-negative pathogens has become a global concern for health workers worldwide. In one of our earlier studies, a Klebsiella pneumoniae-carbapenemase-2 producing strain was induced with meropenem to explore differentially expressed proteins under induced and uninduced conditions. There is, LysM domain BON family protein, was found over 12-fold expressed under the induced state. A hypothesis was proposed that LysM domain protein might have an affinity towards carbapenem antibiotics making them unavailable to bind with their target. Hence, we initiated a study to understand the binding mode of carbapenem with LysM domain protein. MICs of imipenem and meropenem against LysM clone were increased by several folds as compared to NP-6 clinical strain as well as DH5 α (PET-28a KPC-2) clone. This study further revealed a strong binding of both antibiotics to LysM domain protein. Molecular simulation studies of LysM domain protein with meropenem and imipenem for 80 ns has also showed stable structure. We concluded that overexpressed LysM domain under induced condition interacted with carbapenems, leading to enhanced resistance as proved by high MIC values. Hence, the study proved the proposed hypothesis that the LysM domain plays a significant role in the putative mechanism of antibiotics resistance.
    Matched MeSH terms: Imipenem/pharmacology
  7. Susceptibility patterns of anaerobes isolated from clinical specimens in tertiary Hospital, Malaysia
    Ishak N, Abdul Wahab Z, Amin Nordin S, Ibrahim R
    Malays J Pathol, 2020 Aug;42(2):245-252.
    PMID: 32860377
    INTRODUCTION: The susceptibility patterns of anaerobes are becoming less predictable due to the emergence of anaerobic resistance trends to antibiotics; hence increasing the importance of the isolation and antimicrobial susceptibility testing of anaerobes.

    MATERIALS AND METHODS: This study investigated the isolation of anaerobes from the clinical specimens of Hospital Sungai Buloh, Malaysia, from January 2015 to December 2015. All isolates were identified using the API 20A system (bioMérieux, France). Antimicrobial susceptibility testing was performed using the E-test (bioMérieux, France).

    RESULTS: The proportion of obligate anaerobes isolated from the clinical specimens was 0.83%. The Gram-positive anaerobes were most susceptible to vancomycin and imipenem, showing 100% sensitivity to these antimicrobials, followed by clindamycin (86.3%), penicillin (76.7%), and metronidazole (48.9%). Meanwhile, Gram-negative anaerobes were most susceptible to metronidazole (96%) followed by imipenem (89%), clindamycin (79%), and ampicillin (32%). The present study also showed that 3 out of 12 Bacteroides fragilis isolates were resistant to imipenem.

    CONCLUSION: This study demonstrated the differences in the susceptibility patterns of anaerobes towards commonly used antimicrobials for the treatment of anaerobic infections. In summary, continuous monitoring of antimicrobial resistance trends among anaerobes is needed to ensure the appropriateness of treatment.

    Matched MeSH terms: Imipenem/pharmacology
  8. Carbapenem-resistant Pseudomonas aeruginosa in malaysia producing IMP-7 beta-lactamase
    Ho SE, Subramaniam G, Palasubramaniam S, Navaratnam P
    Antimicrob Agents Chemother, 2002 Oct;46(10):3286-7.
    PMID: 12234862
    We have isolated and identified a carbapenem-resistant Pseudomonas aeruginosa strain from Malaysia that produces an IMP-7 metallo-beta-lactamase. This isolate showed high-level resistance to meropenem and imipenem, the MICs of which were 256 and 128 micro g/ml, respectively. Isoelectric focusing analyses revealed pI values of >9.0, 8.2, and 7.8, which indicated the possible presence of IMP and OXA. DNA sequencing confirmed the identity of the IMP-7 determinant.
    Matched MeSH terms: Imipenem/pharmacology
  9. Fulltext Antimicrobial susceptibility and genetic characterisation of Burkholderia pseudomallei isolated from Malaysian patients
    Khosravi Y, Vellasamy KM, Mariappan V, Ng SL, Vadivelu J
    ScientificWorldJournal, 2014;2014:132971.
    PMID: 25379514 DOI: 10.1155/2014/132971
    Burkholderia pseudomallei, the causative agent of melioidosis, is intrinsically resistant to many antibiotics. Ceftazidime (CAZ), the synthetic β-lactam, is normally used as the first-line antibiotic therapy for treatment of melioidosis. However, acquired CAZ resistance can develop in vivo during treatment with CAZ, leading to mortality if therapy is not switched to a different antibiotic(s) in a timely manner. In this study, susceptibilities of 81 B. pseudomallei isolates to nine different antimicrobial agents were determined using the disk diffusion method, broth microdilution test and Etest. Highest percentage of susceptibility was demonstrated to CAZ, amoxicillin/clavulanic acid, meropenem, imipenem, and trimethoprim/sulfamethoxazole. Although these drugs demonstrated the highest percentage of susceptibility in B. pseudomallei, the overall results underline the importance of the emergence of resistance in this organism. PCR results showed that, of the 81 B. pseudomallei, six multidrug resistant (MDR) isolates carried bpeB, amrB, and BPSS1119 and penA genes. Genotyping of the isolates using random amplified polymorphic DNA analysis showed six different PCR fingerprinting patterns generated from the six MDR isolates clusters (A) and eight PCR fingerprinting patterns generated for the remaining 75 non-MDR isolates clusters (B).
    Matched MeSH terms: Imipenem/pharmacology
  10. Metallo-beta-lactamase-producing imipenem-resistant Pseudomonas aeruginosa clinical isolates in a university teaching hospital in Malaysia: detection of IMP-7 and first identification of IMP-4, VIM-2, and VIM-11
    Khosravi Y, Tee Tay S, Vadivelu J
    Diagn Microbiol Infect Dis, 2010 Jul;67(3):294-6.
    PMID: 20462725 DOI: 10.1016/j.diagmicrobio.2010.02.010
    Ninety (n = 90) imipenem-resistant Pseudomonas aeruginosa (IRPA) clinical isolates collected randomly during 2005 to 2008 from University Malaya Medical Center were assessed for the presence of different variants of metallo-beta-lactamase (MBL) genes. Polymerase chain reaction (PCR) assay detected 32 (n = 32) MBL gene PCR-positive isolates with the presence of bla(IMP) gene in 14 (n = 14) and bla(VIM) in 18 (n = 18) isolates. Four allelic variants, bla(IMP-7) (12 isolates), bla(IMP-4) (2 isolates), bla(VIM-2) (17 isolates), and bla(VIM-11) (1 isolate), of MBL genes were identified. This study is the first report of detection of bla(IMP-4), bla(VIM-2), and bla(VIM-11) MBL genes from IRPA clinical isolates in Malaysia.

    Study site: University Malaya Medical Center (UMMC)
    Matched MeSH terms: Imipenem/pharmacology*
  11. Imipenem-resistance in Klebsiella pneumoniae in Malaysia due to loss of OmpK36 outer membrane protein coupled with AmpC hyperproduction
    Palasubramaniam S, Karunakaran R, Gin GG, Muniandy S, Parasakthi N
    Int J Infect Dis, 2007 Sep;11(5):472-4.
    PMID: 17337225
    Matched MeSH terms: Imipenem/pharmacology*
  12. Characterization of multidrug-resistant and extended-spectrum beta-lactamase-producing Klebsiella pneumoniae strains from Malaysian hospitals
    Lim KT, Yeo CC, Md Yasin R, Balan G, Thong KL
    J Med Microbiol, 2009 Nov;58(Pt 11):1463-1469.
    PMID: 19589908 DOI: 10.1099/jmm.0.011114-0
    The emergence of multidrug-resistant (MDR) and extended-spectrum beta-lactamase (ESBL)-producing Klebsiella pneumoniae poses a serious antibiotic management problem as resistance genes are easily transferred from one organism to another. Fifty-one strains of K. pneumoniae isolated from sporadic cases in various hospitals throughout Malaysia were analysed by antimicrobial susceptibility testing, PCR detection of ESBL-encoding genes and DNA fingerprinting. Although 27 of the 51 K. pneumoniae strains were MDR (i.e. resistant to three or more classes of antibiotics), the majority of the strains (98 %) were sensitive to imipenem. PCR detection using ESBL gene-specific primers showed that 46 of the K. pneumoniae strains harboured bla(SHV), 19 harboured bla(CTX-M), 5 harboured bla(OXA-1) and 4 harboured bla(TEM-1). Class 1 integron-encoded intI1 integrase was detected in 21 of the 51 K. pneumoniae strains and amplification of the integron 5'CS region showed the presence of several known antibiotic resistance gene cassettes of various sizes. Results of conjugation and transformation experiments indicated that some of the ESBL-encoding genes (i.e. bla(SHV), bla(CTX-M) and bla(TEM-1)) were transmissible and were likely plasmid-encoded. DNA fingerprinting using PFGE and PCR-based methods indicated that the 51 K. pneumoniae strains were genetically diverse and heterogeneous.
    Matched MeSH terms: Imipenem/pharmacology
  13. Fulltext Imipenem Treatment Induces Expression of Important Genes and Phenotypes in a Resistant Acinetobacter baumannii Isolate
    Dhabaan GN, AbuBakar S, Cerqueira GM, Al-Haroni M, Pang SP, Hassan H
    Antimicrob Agents Chemother, 2015 Dec 14;60(3):1370-6.
    PMID: 26666943 DOI: 10.1128/AAC.01696-15
    Acinetobacter baumannii has emerged as a notorious multidrug-resistant pathogen, and development of novel control measures is of the utmost importance. Understanding the factors that play a role in drug resistance may contribute to the identification of novel therapeutic targets. Pili are essential for A. baumannii adherence to and biofilm formation on abiotic surfaces as well as virulence. In the present study, we found that biofilm formation was significantly induced in an imipenem-resistant (Imp(r)) strain treated with a subinhibitory concentration of antibiotic compared to that in an untreated control and an imipenem-susceptible (Imp(s)) isolate. Using microarray and quantitative PCR analyses, we observed that several genes responsible for the synthesis of type IV pili were significantly upregulated in the Imp(r) but not in the Imp(s) isolate. Notably, this finding is corroborated by an increase in the motility of the Imp(r) strain. Our results suggest that the ability to overproduce colonization factors in response to imipenem treatment confers biological advantage to A. baumannii and may contribute to clinical success.
    Matched MeSH terms: Imipenem/pharmacology*
  14. Fulltext Elucidating the survival and response of carbapenem resistant Klebsiella pneumoniae after exposure to imipenem at sub-lethal concentrations
    Low YM, Chong CW, Yap IKS, Chai LC, Clarke SC, Ponnampalavanar S, et al.
    Pathog Glob Health, 2018 10;112(7):378-386.
    PMID: 30380366 DOI: 10.1080/20477724.2018.1538281
    The increasing prevalence of antibiotic resistant pathogens poses a serious threat to global health. However, less emphasis has been placed to co-relate the gene expression and metabolism of antibiotic resistant pathogens. This study aims to elucidate gene expression and variations in metabolism of multidrug resistant Klebsiella pneumoniae after exposure to antibiotics. Phenotypic responses of three genotypically distinct carbapenem resistant Klebsiella pneumoniae (CRKP) strains untreated and treated with sub-lethal concentrations of imipenem were investigated via phenotype microarrays (PM). The gene expression and metabolism of the strain harboring blaNDM-1 before and after exposure to sub-lethal concentration of imipenem were further investigated by RNA-sequencing (RNA-Seq) and 1H NMR spectroscopy respectively. Most genes related to cell division, central carbon metabolism and nucleotide metabolism were downregulated after imipenem treatment. Similarly, 1H NMR spectra obtained from treated CRKP showed decrease in levels of bacterial end products (acetate, pyruvate, succinate, formate) and metabolites involved in nucleotide metabolism (uracil, xanthine, hypoxanthine) but elevated levels of glycerophosphocholine. The presence of anserine was also observed for the treated CRKP while FAPγ-adenine and methyladenine were only present in untreated bacterial cells. As a conclusion, the studied CRKP strain exhibited decrease in central carbon metabolism, cell division and nucleotide metabolism after exposure to sub-lethal concentrations of imipenem. The understanding of the complex biological system of this multidrug resistant bacterium may help in the development of novel strategies and potential targets for the management of the infections.
    Matched MeSH terms: Imipenem/pharmacology*
  15. Fulltext Risk factors and outcomes of imipenem-resistant Acinetobacter bloodstream infection in North-Eastern Malaysia
    Deris ZZ, Shafei MN, Harun A
    Asian Pac J Trop Biomed, 2011 Aug;1(4):313-5.
    PMID: 23569782 DOI: 10.1016/S2221-1691(11)60050-6
    To determine the risk factors and outcomes of imipenem-resistant Acinetobacter baumannii (IRAB) bloodstream infection (BSI) cases, since there is very little publication on Acinetobacter baumannii infections from Malaysia.
    Matched MeSH terms: Imipenem/pharmacology
  16. Fulltext Characterization of multidrug resistant ESBL-producing Escherichia coli isolates from hospitals in Malaysia
    Lim KT, Yasin R, Yeo CC, Puthucheary S, Thong KL
    J Biomed Biotechnol, 2009;2009:165637.
    PMID: 19672454 DOI: 10.1155/2009/165637
    The emergence of Escherichia coli that produce extended spectrum beta-lactamases (ESBLs) and are multidrug resistant (MDR) poses antibiotic management problems. Forty-seven E. coli isolates from various public hospitals in Malaysia were studied. All isolates were sensitive to imipenem whereas 36 were MDR (resistant to 2 or more classes of antibiotics). PCR detection using gene-specific primers showed that 87.5% of the ESBL-producing E. coli harbored the blaTEM gene. Other ESBL-encoding genes detected were blaOXA, blaSHV, and blaCTX-M. Integron-encoded integrases were detected in 55.3% of isolates, with class 1 integron-encoded intI1 integrase being the majority. Amplification and sequence analysis of the 5'CS region of the integrons showed known antibiotic resistance-encoding gene cassettes of various sizes that were inserted within the respective integrons. Conjugation and transformation experiments indicated that some of the antibiotic resistance genes were likely plasmid-encoded and transmissible. All 47 isolates were subtyped by PFGE and PCR-based fingerprinting using random amplified polymorphic DNA (RAPD), repetitive extragenic palindromes (REPs), and enterobacterial repetitive intergenic consensus (ERIC). These isolates were very diverse and heterogeneous. PFGE, ERIC, and REP-PCR methods were more discriminative than RAPD in subtyping the E. coli isolates.
    Matched MeSH terms: Imipenem/pharmacology
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