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1.
BMC Microbiol ; 22(1): 290, 2022 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-36463105

RESUMO

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.


Assuntos
Acinetobacter baumannii , Acinetobacter baumannii/genética , Doripenem , Meropeném/farmacologia , Inosina Monofosfato , Simulação de Acoplamento Molecular , Imipenem/farmacologia , Carbapenêmicos/farmacologia , Antibacterianos/farmacologia
2.
Enferm Infecc Microbiol Clin (Engl Ed) ; 40(10): 568-571, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36464474

RESUMO

INTRODUCTION: Here, we propose a novel modified Carba NP test for detecting KPC-producing Enterobacterales using imipenem/relebactam. MATERIAL AND METHODS: The test performance was evaluated in a random selection of 160 previously molecularly characterized clinical isolates carrying the 110 blaKPC, 1 blaGES, 12 blaVIM, 4 blaIMP, 3 blaNDM and 42 blaOXA-48-like genes. The proposed method relies on the detection of imipenem hydrolysis in an imipenem/relebactam antibiotic solution and subsequent visual interpretation by color change. RESULTS: All class A producing Enterobacterales (111/111) were detected using imipenem/relebactam as no visual appreciation of color change was perceived due to a nule hydrolysis of imipenem in the antibiotic solution. Overall, the assay showed 100% sensitivity (111/111) and specificity (69/69) for detecting class A KPC-producing Enterobacterales. DISCUSSION: The biochemical assay provides very reliable results for detecting KPC-producing Enterobacterales, with a turnaround time of less than 1 hour, minimum handling and no specialized equipment required.


Assuntos
Gammaproteobacteria , Imipenem/farmacologia , Antibacterianos/farmacologia , Compostos Azabicíclicos
3.
J Med Chem ; 65(24): 16234-16251, 2022 12 22.
Artigo em Inglês | MEDLINE | ID: mdl-36475645

RESUMO

With the emergence and rapid spreading of NDM-1 and existence of clinically relevant VIM-1 and IMP-1, discovery of pan inhibitors targeting metallo-beta-lactamases (MBLs) became critical in our battle against bacterial infection. Concurrent with our fragment and high-throughput screenings, we performed a knowledge-based search of known metallo-beta-lactamase inhibitors (MBLIs) to identify starting points for early engagement of medicinal chemistry. A class of compounds exemplified by 11, discovered earlier as B. fragilis metallo-beta-lactamase inhibitors, was selected for in silico virtual screening. From these efforts, compound 12 was identified with activity against NDM-1 only. Initial exploration on metal binding design followed by structure-guided optimization led to the discovery of a series of compounds represented by 23 with a pan MBL inhibition profile. In in vivo studies, compound 23 in combination with imipenem (IPM) robustly lowered the bacterial burden in a murine infection model and became the lead for the invention of MBLI clinical candidates.


Assuntos
Infecções Bacterianas , Inibidores de beta-Lactamases , Animais , Camundongos , Inibidores de beta-Lactamases/farmacologia , Inibidores de beta-Lactamases/uso terapêutico , Inibidores de beta-Lactamases/química , Imipenem/farmacologia , Imipenem/uso terapêutico , beta-Lactamases/metabolismo , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Antibacterianos/química , Testes de Sensibilidade Microbiana
4.
PLoS One ; 17(12): e0279715, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36584159

RESUMO

AIM: To describe the occurrence of carbapenem resistance among multidrug-resistant (MDR) Escherichia coli and Klebsiella pneumoniae isolated from clinical specimens in Accra using phenotypic and genotypic methods. METHODOLOGY: The study was cross-sectional, involving 144 clinical MDR E. coli and K. pneumoniae isolates recovered from the Central Laboratory of the Korle Bu Teaching Hospital (KBTH). The isolates were re-cultured bacteriologically, identified using standard biochemical tests, and subjected to antibiotic susceptibility testing using the Kirby-Bauer method. Carbapenem resistance was determined based on imipenem, meropenem, and ertapenem zones of inhibition, as well as minimum inhibitory concentrations (MICs). Carbapenemase production was determined phenotypically by modified Hodge test (MHT) and modified carbapenem inactivation method (mCIM), and genotypically with multiplex PCR targeting the blaKPC, blaIMP, blaNDM, blaVIM, and blaOXA-48 genes. RESULTS: Of the 144 MDR isolates, 69.4% were E. coli, and 30.6% were K. pneumoniae. The distribution of antimicrobial resistance rates among them was ampicillin (97.2%), cefuroxime (93.1%), sulfamethoxazole-trimethoprim (86.8%), tetracycline (85.4%), cefotaxime and cefpodoxime (77.1% each), amoxicillin-clavulanate (75%), ceftriaxone (73.6%), ciprofloxacin (70.8%), levofloxacin (66.0%), cefepime (65.3%), ceftazidime (64.6%), gentamicin (48.6), piperacillin-tazobactam (40.3%), cefoxitin (14.6%), amikacin (13.9%), ertapenem and meropenem (5.6% each), and imipenem (2.8%). In total, 5.6% (8/144) of them were carbapenem-resistant (carbapenem MIC range = 0.094-32.0 µg/ml), with 75% (6/8) of these testing positive by the phenotypic tests and 62.5% (5/8) by the genotypic test (of which 80% [4/5] carried blaOXA-48 and 20% (1/5) blaNDM). The blaVIM, blaIMP, and blaKPC genes were not detected. CONCLUSION: Although the rates of antibiotic resistance among the isolates were high, the prevalence of carbapenemase producers was low. The finding of blaOXA-48 and blaNDM warrants upscaling of antimicrobial resistance surveillance programmes and fortification of infection prevention and control programmes in the country.


Assuntos
Enterobacteriáceas Resistentes a Carbapenêmicos , Klebsiella pneumoniae , Meropeném , Ertapenem , Escherichia coli , Gana/epidemiologia , Estudos Transversais , beta-Lactamases/genética , Proteínas de Bactérias/genética , Antibacterianos/farmacologia , Carbapenêmicos/farmacologia , Enterobacteriáceas Resistentes a Carbapenêmicos/genética , Imipenem/farmacologia , Testes de Sensibilidade Microbiana
5.
Molecules ; 27(23)2022 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-36500645

RESUMO

Methicillin-resistant Staphylococcus aureus (MRSA) is one of the leading causes of infection worldwide. Clove oil's ability to inhibit the growth of MRSA was studied through in vitro and in vivo studies. The phytochemical components of clove oil were determined through gas chromatography-mass spectrometry (GC-MS) analysis. The antibacterial effects of clove oil and its interaction with imipenem were determined by studying MIC, MBC, and FIC indices in vitro. The in vivo wound-healing effect of the clove oil and infection control were determined using excision wound model rats. The GC-MS analysis of clove oil revealed the presence of 16 volatile compounds. Clove oil showed a good antibacterial effect in vitro but no interaction was observed with imipenem. Clove bud oil alone or in combination with imipenem healed wounds faster and reduced the microbial load in wounds. The findings of this study confirmed the antibacterial activity of clove oil in vitro and in vivo and demonstrated its interaction with imipenem.


Assuntos
Staphylococcus aureus Resistente à Meticilina , Óleos Voláteis , Syzygium , Infecção dos Ferimentos , Ratos , Animais , Syzygium/química , Óleo de Cravo/farmacologia , Óleo de Cravo/química , Imipenem/farmacologia , Óleos Voláteis/farmacologia , Óleos Voláteis/química , Testes de Sensibilidade Microbiana , Antibacterianos/farmacologia , Antibacterianos/química
6.
BMC Microbiol ; 22(1): 284, 2022 11 29.
Artigo em Inglês | MEDLINE | ID: mdl-36443681

RESUMO

BACKGROUND: Enterobacter cloacae complex (ECC) is a common opportunistic pathogen and is responsible for causing various infections in humans. Owing to its inducible chromosomal AmpC ß-lactamase (AmpC), ECC is inherently resistant to the 1st- and 2nd- generation cephalosporins. However, whether ß-lactams antibiotics enhance ECC resistance remains unclear. RESULTS: In this study, we found that subinhibitory concentrations (SICs) of cefazolin (CFZ) and imipenem (IMP) can advance the expression of AmpC and enhance its resistance towards ß-lactams through NagZ in Enterobacter cloacae (EC). Further, AmpC manifested a substantial upregulation in EC in response to SICs of CFZ and IMP. In nagZ knockout EC (ΔnagZ), the resistance to ß-lactam antibiotics was rather weakened and the effect of CFZ and IMP on AmpC induction was completely abrogated. NagZ ectopic expression can rescue the induction effects of CFZ and IMP on AmpC and increase ΔnagZ resistance. More importantly, CFZ and IMP have the potential to induce the expression of AmpR's target genes in a NagZ-dependent manner. CONCLUSIONS: Our findings suggest that NagZ is a critical determinant for CFZ and IMP to promote AmpC expression and resistance and that CFZ and IMP should be used with caution since they may aggravate ECC resistance. At the same time, this study further improves our understanding of resistance mechanisms in ECC.


Assuntos
Cefazolina , Imipenem , Humanos , Imipenem/farmacologia , Cefazolina/farmacologia , Enterobacter cloacae/genética , Inosina Monofosfato , Monobactamas , Antibacterianos/farmacologia
7.
Curr Med Sci ; 42(5): 1106-1110, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36184727

RESUMO

OBJECTIVE: To evaluate the impact of Antimicrobial Stewardship Programs (ASPs) on antibiotic use and drug resistance. METHODS: This was a retrospective, multicenter, management intervention study. The data from 85 maternity hospitals (maternal and child health care hospitals) in Hubei province from 2012 to 2019 were collected. The indicators related to antimicrobial drug use included the utilization rate of different grades of antimicrobial drugs, the intensity of antimicrobial agent use, the rational use of prophylactic antimicrobial agents before class I surgical incision, and pathogenic detection and consultation rates before antimicrobial drug use. RESULTS: Since the implementation, the purchase of antimicrobial agents in hospitals has been maintained within the prescribed range, and the defined daily dose system (DDDs) of antimicrobial agents has been reduced, prophylactic use and accurate treatment of antimicrobial agents related to class I surgical incision have been more reasonable. With the implementation of ASPs, the detection rate of imipenem-resistant Acinetobacter baumannii, cefotaxime-resistant Escherichia coli, and methicillin-resistant Staphylococcus aureus has been decreased in China from national bacterial resistance surveillance data. CONCLUSION: ASPs have positive effects on antibiotic use and drug resistance in 85 maternity hospitals (maternal and child health care hospitals).


Assuntos
Gestão de Antimicrobianos , Staphylococcus aureus Resistente à Meticilina , Ferida Cirúrgica , Gravidez , Criança , Feminino , Humanos , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Saúde da Criança , Estudos Retrospectivos , Ferida Cirúrgica/tratamento farmacológico , Hospitais , Escherichia coli , Resistência a Medicamentos , Cefotaxima/farmacologia , Imipenem/farmacologia
8.
Klin Lab Diagn ; 67(10): 594-599, 2022 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-36315175

RESUMO

One of the reasons for the emergence of highly resistant strains is associated with the ability of bacteria to form biofilms on various surfaces. The formation of a biofilm by pathogens leads to a decrease in the activity of the antibiotic, an increase in the time for the production of stress response genes by bacteria, and, as a result, an increase in antimicrobial tolerance. To investigate the effect of imipenem and cefepime on the activity of biofilm forms of K. pneumoniae bacteria isolated from the wounds of patients with chronic osteomyelitis. The object of the study is clinical strains of K. pneumoniae isolated from the wounds of patients with chronic osteomyelitis. In the control series, the level of biofilm formation of K. pneumoniae strains was assessed after 48 hours of cultivation on coverslips and 96-well polystyrene plates. In the second and third series, the biofilm form of K. pneumoniae bacteria was exposed to imipenem and cefepime, and after 24 hours the activity of biofilm formation was assessed according to previously developed criteria. The structure of the emerging biofilm on the surface of the coverslip in all series of the experiment was represented by single adherent cells and microcolonies of various sizes. Cultivation with antibiotics led to a decrease in the number of microcolonies ranging in size from 10 to 10,000 µm2 in the second and third series, however, significant differences from the control series were found only when exposed to cefepime. The intensity of film formation of K. pneumoniae in the control series by the tablet method was 0.350 (0.334; 0.368) units opt.pl. When cultivating biofilms together with antibacterial drugs, the biofilm-forming activity after 24 hours of the experiment was significantly lower than in the control group in all experimental series. K. pneumoniae bacteria isolated from patients with chronic osteomyelitis, when cultivated on polystyrene plates and on the surface of coverslips, actively form a biofilm, exhibiting highly adhesive properties. The studied antibiotics were shown to have a bacteriostatic effect on biofilm forms of K. pneumoniae bacteria. The bactericidal effect of imipenem and cefepime on biofilm forms was not revealed.


Assuntos
Osteomielite , Poliestirenos , Humanos , Testes de Sensibilidade Microbiana , Cefepima/farmacologia , Poliestirenos/farmacologia , Klebsiella pneumoniae , Biofilmes , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Osteomielite/tratamento farmacológico , Monobactamas/farmacologia , Bactérias , Imipenem/farmacologia , Imipenem/uso terapêutico
9.
BMC Microbiol ; 22(1): 247, 2022 10 11.
Artigo em Inglês | MEDLINE | ID: mdl-36221063

RESUMO

BACKGROUND: Proteus mirabilis is an opportunistic pathogen, causing a variety of community-acquired and nosocomial illnesses. It poses a potential threat to patients via the production of ß-lactamases, which decrease the efficacy of antimicrobial treatment and impair the management of its pathogenicity. Hence, this study was established to determine the prevalence of extended-spectrum ß-lactamases (ESBLs), AmpC, and carbapenemases of P. mirabilis isolated from various clinical specimens. RESULTS: Proteus mirabilis was identified in 20.7% (58/280) of specimens. ESBL producers were present at a rate of 51.7% (30/58). All AmpC-positive isolates (n = 20) produced ESBLs as well, so 66.7% of ESBL-producing isolates coproduced AmpC enzymes. The modified Hodge test confirmed carbapenemase production in six out of seven imipenem nonsusceptible isolates. Of these, only two (5.7%) isolates were also ESBL-and AmpC-positive. Antibiotic resistance reached the highest level for cotrimoxazole (62.1%, n = 36/58 isolates) and the lowest for imipenem (12.1%, n = 7/58 isolates). The levels of multidrug-resistant (MDR) was 41.4% among the tested isolates. The blaSHV (83.3%), blaAmpC (80%), and blaVIM-1 (50%) were the most detected genes in phenotypically confirmed ESBL-, AmpC-, and carbapenemase-producing isolates, respectively. Besides, more than a half of the tested P. mirabilis strains (53%) coproduced ESBLs and AmpC. Moreover, two isolates coproduced ESBLs and AmpC together with carbapenemases. Furthermore, dendrogram analysis showed great genetic divergence based on the 21 different enterobacterial repetitive intergenic consensus (ERIC) patterns (P1-P21) through the 34 ß-lactamase producers. ERIC analysis distinguished clonal similarities between isolates 21 and 22 in P2 and 9 and 10 in P4, which were isolated from the same clinical source and possessed similar patterns of ß-lactamase-encoding genes. CONCLUSION: Hence, there is an urgent need to monitor hospitalized patients and improve healthcare in order to reduce the incidence of infection and outbreaks of infection with antibiotic-resistant Proteus.


Assuntos
Proteus mirabilis , Combinação Trimetoprima e Sulfametoxazol , Antibacterianos/farmacologia , Proteínas de Bactérias/genética , Enterobacteriaceae/genética , Humanos , Imipenem/farmacologia , Testes de Sensibilidade Microbiana , Prevalência , Proteus mirabilis/genética , beta-Lactamases/genética
10.
Sci Rep ; 12(1): 16814, 2022 10 07.
Artigo em Inglês | MEDLINE | ID: mdl-36207358

RESUMO

Multidrug resistant (MDR) P. aeruginosa accounts for 35% of all P. aeruginosa isolated from respiratory samples of patients with cystic fibrosis (CF). The usefulness of ß-lactam antibiotics for treating CF, such as carbapenems and later generation cephalosporins, is limited by the development of antibacterial resistance. A proven treatment approach is the combination of a ß-lactam antibiotic with a ß-lactamase inhibitor. New ß-lactam/ß-lactamase inhibitor combinations are available, but data are lacking regarding the susceptibility of MDR CF-associated P. aeruginosa (CFPA) to these new combination therapies. In this study we determined MIC values for three new combinations; imipenem-relebactam (I-R), ceftazidime-avibactam (CZA), and ceftolozane-tazobactam (C/T) against MDR CFPA (n = 20). The MIC90 of I-R, CZA, and C/T was 64/4, 32/4, and 16/8 (all µg/mL), respectively. The susceptibility of isolates to imipenem was not significantly improved with the addition of relebactam (p = 0.68). However, susceptibility to ceftazidime was significantly improved with the addition of avibactam (p < 0.01), and the susceptibility to C/T was improved compared to piperacillin/tazobactam (p < 0.05) These data provide in vitro evidence that I-R may not be any more effective than imipenem monotherapy against MDR CFPA. The pattern of susceptibility observed for CZA and C/T in the current study was similar to data previously reported for non-CF-associated MDR P. aeruginosa.


Assuntos
Ceftazidima , Infecções por Pseudomonas , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Compostos Azabicíclicos , Carbapenêmicos/farmacologia , Ceftazidima/uso terapêutico , Cefalosporinas , Combinação de Medicamentos , Farmacorresistência Bacteriana Múltipla , Humanos , Imipenem/farmacologia , Lactamas/farmacologia , Testes de Sensibilidade Microbiana , Monobactamas/farmacologia , Combinação Piperacilina e Tazobactam/uso terapêutico , Infecções por Pseudomonas/tratamento farmacológico , Infecções por Pseudomonas/microbiologia , Pseudomonas aeruginosa , Tazobactam/farmacologia , Tazobactam/uso terapêutico , Inibidores de beta-Lactamases/farmacologia , Inibidores de beta-Lactamases/uso terapêutico
11.
Int J Mol Sci ; 23(20)2022 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-36293559

RESUMO

Antibiotics at suboptimal doses promote biofilm formation and the development of antibiotic resistance. The underlying molecular mechanisms, however, were not investigated. Here, we report the effects of sub-minimum inhibitory concentrations (sub-MICs) of imipenem and colistin on genes associated with biofilm formation and biofilm-specific antibiotic resistance in a multidrug-tolerant clinical strain of Acinetobacter baumannii Sequence Type (ST) 1894. Comparative transcriptome analysis was performed in untreated biofilm and biofilm treated with sub-MIC doses of imipenem and colistin. RNA sequencing data showed that 78 and 285 genes were differentially expressed in imipenem and colistin-treated biofilm cells, respectively. Among the differentially expressed genes (DEGs), 48 and 197 genes were upregulated exclusively in imipenem and colistin-treated biofilm cells, respectively. The upregulated genes included those encoding matrix synthesis (pgaB), multidrug efflux pump (novel00738), fimbrial proteins, and homoserine lactone synthase (AbaI). Upregulation of biofilm-associated genes might enhance biofilm formation when treated with sub-MICs of antibiotics. The downregulated genes include those encoding DNA gyrase (novel00171), 30S ribosomal protein S20 (novel00584), and ribosome releasing factor (RRF) were downregulated when the biofilm cells were treated with imipenem and colistin. Downregulation of these genes affects protein synthesis, which in turn slows down cell metabolism and makes biofilm cells more tolerant to antibiotics. In this investigation, we also found that 5 of 138 small RNAs (sRNAs) were differentially expressed in biofilm regardless of antibiotic treatment or not. Of these, sRNA00203 showed the highest expression levels in biofilm. sRNAs regulate gene expression and are associated with biofilm formation, which may in turn affect the expression of biofilm-specific antibiotic resistance. In summary, when biofilm cells were exposed to sub-MIC doses of colistin and imipenem, coordinated gene responses result in increased biofilm production, multidrug efflux pump expression, and the slowdown of metabolism, which leads to drug tolerance in biofilm. Targeting antibiotic-induced or repressed biofilm-specific genes represents a new strategy for the development of innovative and effective treatments for biofilm-associated infections caused by A. baumannii.


Assuntos
Infecções por Acinetobacter , Acinetobacter baumannii , Humanos , Colistina/farmacologia , Colistina/uso terapêutico , Imipenem/farmacologia , Imipenem/uso terapêutico , Infecções por Acinetobacter/tratamento farmacológico , Virulência , DNA Girase , Testes de Sensibilidade Microbiana , Biofilmes , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Farmacorresistência Bacteriana Múltipla/genética
12.
Sci Rep ; 12(1): 18258, 2022 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-36309535

RESUMO

GBHs are the most widely used herbicides for weed control worldwide that potentially affect microorganisms, but the role of their sublethal exposure in the development of antibiotic resistance of Pseudomonas aeruginosa is still not fully investigated. Here, the effects of glyphosate acid (GLY), five glyphosate-based herbicides (GBHs), and POE(15), a formerly used co-formulant, on susceptibility to imipenem, a potent carbapenem-type antibiotic, in one clinical and four non-clinical environmental P. aeruginosa isolates were studied. Both pre-exposure in broth culture and co-exposure in solid media of the examined P. aeruginosa strains with 0.5% GBHs resulted in a decreased susceptibility to imipenem, while other carbapenems (doripenem and meropenem) retained their effectiveness. Additionally, the microdilution chequerboard method was used to examine additive/antagonistic/synergistic effects between GLY/POE(15)/GBHs and imipenem by determining the fractional inhibitory concentration (FIC) indexes. Based on the FIC index values, glyphosate acid and Total demonstrated a potent antagonistic effect in all P. aeruginosa strains. Dominator Extra 608 SL and Fozat 480 reduced the activity of imipenem in only one strain (ATCC10145), while POE(15) and three other GBHs did not have any effect on susceptibility to imipenem. Considering the simultaneous presence of GBHs and imipenem in various environmental niches, the detected interactions between these chemicals may affect microbial communities. The mechanisms of the glyphosate and GBH-induced imipenem resistance in P. aeruginosa are yet to be investigated.


Assuntos
Herbicidas , Pseudomonas aeruginosa , Imipenem/farmacologia , Herbicidas/farmacologia , Glicina/farmacologia , Carbapenêmicos/farmacologia , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Testes de Sensibilidade Microbiana
13.
Antimicrob Resist Infect Control ; 11(1): 121, 2022 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-36182905

RESUMO

BACKGROUND: The coronavirus disease 2019 seems to change antibiotic resistance pattern. Certain conditions in the Covid-19 era may be contributing to the rise of antimicrobial resistance (AMR). Due to the limited information on the impact of Covid-19 on antimicrobial resistance (AMR), the purpose of this research was to investigate the trend in antimicrobial resistance changes of E. coli, P. aeruginosa, K. pneumoniae, and A. baumannii in Hasheminezhad hospital. This hospital was a Corona center in Mashhad at the onset of this epidemic. METHODS: 1672 clinical samples were collected between January 21, 2020 and January 30, 2022from patients hospitalized at Hasheminezhad Hospital in Mashhad, Conventional microbiological procedures for identifying gram-negative bacteria and antibiotic susceptibility testing were used, according to the clinical and laboratory standards institute (CLSI) 2021. The two years of the pandemic, from the initial stage of the outbreak until the 6th peak, (January 2020 to and January 2022) were divided into 9 periods according to the seasons. RESULTS: Highest resistance rates were seen in E. coli (615 samples), K. pneumoniae (351 samples), P. aeruginosa (362 samples) and A. baumannii (344 samples) to Ampicillin (89.6%), Ampicillin (98%), Imipenem (91.8%), and Ceftazidime (94.6%), respectively. The largest change in antibiotic resistance was seen between Summer 2020 and Summer 2021 for K. pneumoniae with about a 30% rise in antibiotic resistance to Ceftriaxone. CONCLUSIONS: All 4 species evaluated in this study, have shown rising AMR rates during the first year of the pandemic in the northeast of Iran. This study revealed that E. coli, P. aeruginosa, K. pneumoniae, and A. baumannii strains in Northern Iran have a higher level of antibiotic resistance than what was measured in similar studies conducted before the pandemic. This will further restrict treatment choices and jeopardize global public health.


Assuntos
Acinetobacter baumannii , COVID-19 , Ampicilina/farmacologia , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , COVID-19/epidemiologia , Ceftazidima/farmacologia , Ceftriaxona/farmacologia , Farmacorresistência Bacteriana , Escherichia coli , Humanos , Imipenem/farmacologia , Irã (Geográfico)/epidemiologia , Klebsiella pneumoniae , Testes de Sensibilidade Microbiana , Pandemias , Pseudomonas aeruginosa
14.
Klin Mikrobiol Infekc Lek ; 28(1): 18-21, 2022 Mar.
Artigo em Eslovaco | MEDLINE | ID: mdl-36183413

RESUMO

The article describes the use of the last-resort carbapenem antibiotic imipenem in combination with relebactam, a novel b-lactamase inhibitor, in the treatment of ventilator-associated pneumonia developing after SARS-CoV-2 infection in a young pregnant patient. The introduction briefly describes the mechanism and spectrum of activity of the antibiotic, including its dosage.


Assuntos
COVID-19 , Pneumonia Associada à Ventilação Mecânica , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Compostos Azabicíclicos , Combinação Imipenem e Cilastatina , Humanos , Imipenem/farmacologia , Imipenem/uso terapêutico , Testes de Sensibilidade Microbiana , Pneumonia Associada à Ventilação Mecânica/tratamento farmacológico , SARS-CoV-2
15.
Antimicrob Agents Chemother ; 66(10): e0091822, 2022 10 18.
Artigo em Inglês | MEDLINE | ID: mdl-36154170

RESUMO

Carbapenem-resistant Enterobacterales, such as KPC-producing Klebsiella pneumoniae, represent a major threat to public health. Novel drug combinations including imipenem-relebactam (IPM-REL) have recently been introduced and have been shown to exhibit excellent activity toward such strains. However, there has recently been reports of the in vivo emergence of IPM-REL resistance in KPC-producing K. pneumoniae. Here, we evaluated, in vitro, the nature of the mutations that lead to IPM-REL resistance in 5 KPC-producing K. pneumoniae strains, including 2 that produce KPC enzymes conferring ceftazidime-avibactam resistance. An in vitro multi-step selection assay was performed and corresponding mutants obtained. Mutations were identified in OmpK36 as well as 2 different mutant derivatives of KPC. Mutant strains exhibited decreased susceptibility to ß-lactams, including the carbapenems, and meropenem-vaborbactam (MEM-VAB). Expression of blaKPC gene variants in an Escherichia coli recombinant strain resulted in a concomitant increased susceptibility to carbapenems and decreased susceptibility to CAZ-AVI, and enzymatic assays showed that the inhibitory activity of both AVI and REL was significantly lowered for both KPC mutants compared to parental enzymes. Complementation assays showed that OmpK36 plays a major role in IPM-REL resistance as well resistance to other ß-lactams and ß-lactam/ß-lactamase inhibitor combinations. Overall, this study showed that (i) IPM-REL resistant strains can be obtained from CAZ-AVI-susceptible or -resistant KPC producers, (ii) selection of IPM-REL resistance has a collateral effect on MEM-VAB susceptibility - indicative of shared resistance mechanisms, (iii) and mutations in the KPC sequence may be obtained using IPM-REL selection leading to the possibility of vertical and horizontal transfer of this resistance trait.


Assuntos
Infecções por Klebsiella , Klebsiella pneumoniae , Humanos , Meropeném/farmacologia , beta-Lactamases/metabolismo , Testes de Sensibilidade Microbiana , Compostos Azabicíclicos/farmacologia , Ceftazidima/farmacologia , Antibacterianos/farmacologia , Inibidores de beta-Lactamases/farmacologia , Cefalosporinas/farmacologia , Carbapenêmicos/farmacologia , Escherichia coli , Combinação de Medicamentos , Imipenem/farmacologia , Proteínas de Bactérias/metabolismo
16.
Ann Med ; 54(1): 2500-2510, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36120867

RESUMO

Objective: To determine the minimum inhibitory concentration (MIC) distribution of antibacterial drugs and the susceptibility of non-tuberculous mycobacterial (NTM) isolates to provide a reference basis for the clinical selection of an effective starting regimen.Methods: The common clinical isolates of NTM in the respiratory tract, which met the standards of the American Thoracic Society for NTM lung disease, were collected. The MICs of 81 isolates were determined using the microbroth dilution method (Thermo Fisher Scientific, USA), as recommended by the Clinical and Laboratory Standards Institute, USA.Results: Included were 43 Mycobacterium avium complex (MAC) strains, 24 M. abscessus complex (MAB) strains, and 14 M. kansasii strains. The sensitivity rates of MAC to clarithromycin and amikacin were 81.4% and 79.1%, respectively, while the sensitivity rates to linezolid and moxifloxacin were only 20.9% and 9.3%; the MIC of rifabutin was the lowest (MIC50% was just 2 µg/mL). After incubation for 3-5 days, the sensitivity rate of MAB to clarithromycin was 87.5%; this decreased to 50% after 14 days' incubation. Most of them were susceptible to amikacin (91.6%), and most were resistant to moxifloxacin (95.8%), ciprofloxacin (95.8%), imipenem (95.8%), amoxicillin/clavulanate (95.8%), tobramycin (79.1%), doxycycline (95.8%) and trimethoprim/sulfamethoxazole (95.8%). intermediate (83.3%) and resistant (16.7%) to cefoxitin. The susceptibility to linezolid was only 33.3%. The sensitivity and resistance breakpoints of tigecycline were set to ≤0.5 and ≥8 µg/mL, respectively, and the sensitivity and resistance rates were 50% and 0%, respectively. M. kansasii was susceptible to clarithromycin, amikacin, linezolid, moxifloxacin, rifampicin and rifabutin (100%).Discussion: In Wenzhou, clarithromycin, amikacin and rifabutin have good antibacterial activity against MAC, while linezolid and moxifloxacin have high resistance. Amikacin and tigecycline have strong antibacterial activity against MAB, while most other antibacterial drugs are resistant to varying degrees. Most antibacterial drugs are susceptible to M. kansasii and have good antibacterial activity.Conclusion: The identification of NTM species and the detection of their MICs have certain guiding values for the treatment of NTM lung disease.Key MessageThe three most common respiratory non-tuberculous mycobacterial (NTM) isolates with clinical significance in the Wenzhou area were tested for drug susceptibility. The broth microdilution method was used to determine the minimum inhibitory concentration distribution of antibacterial drugs and the susceptibility of NTM isolates to provide a reference basis for the clinical selection of an effective starting regimen.


Assuntos
Pneumopatias , Infecções por Mycobacterium não Tuberculosas , Amicacina/farmacologia , Amicacina/uso terapêutico , Amoxicilina , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Cefoxitina/farmacologia , Cefoxitina/uso terapêutico , Ciprofloxacina/farmacologia , Ciprofloxacina/uso terapêutico , Claritromicina/farmacologia , Ácido Clavulânico/farmacologia , Ácido Clavulânico/uso terapêutico , Doxiciclina/farmacologia , Doxiciclina/uso terapêutico , Humanos , Imipenem/farmacologia , Imipenem/uso terapêutico , Linezolida/farmacologia , Linezolida/uso terapêutico , Testes de Sensibilidade Microbiana , Moxifloxacina/farmacologia , Moxifloxacina/uso terapêutico , Infecções por Mycobacterium não Tuberculosas/tratamento farmacológico , Infecções por Mycobacterium não Tuberculosas/microbiologia , Micobactérias não Tuberculosas , Sistema Respiratório , Rifabutina/farmacologia , Rifabutina/uso terapêutico , Rifampina/farmacologia , Rifampina/uso terapêutico , Sulfametoxazol/farmacologia , Sulfametoxazol/uso terapêutico , Tigeciclina/farmacologia , Tigeciclina/uso terapêutico , Tobramicina/farmacologia , Tobramicina/uso terapêutico , Trimetoprima/farmacologia , Trimetoprima/uso terapêutico
17.
J Antimicrob Chemother ; 77(11): 3163-3172, 2022 10 28.
Artigo em Inglês | MEDLINE | ID: mdl-36059128

RESUMO

OBJECTIVES: To study the in vitro activity of imipenem/relebactam and comparators and the imipenem/relebactam resistance mechanisms in a Pseudomonas aeruginosa collection from Portugal (STEP, 2017-18) and Spain (SUPERIOR, 2016-17) surveillance studies. METHODS: P. aeruginosa isolates (n = 474) were prospectively recovered from complicated urinary tract (cUTI), complicated intra-abdominal (cIAI) and lower respiratory tract (LRTI) infections in 11 Portuguese and 8 Spanish ICUs. MICs were determined (ISO broth microdilution). All imipenem/relebactam-resistant P. aeruginosa isolates (n = 30) and a subset of imipenem/relebactam-susceptible strains (n = 32) were characterized by WGS. RESULTS: Imipenem/relebactam (93.7% susceptible), ceftazidime/avibactam (93.5% susceptible) and ceftolozane/tazobactam (93.2% susceptible) displayed comparable activity. The imipenem/relebactam resistance rate was 6.3% (Portugal 5.8%; Spain 8.9%). Relebactam restored imipenem susceptibility to 76.9% (103/134) of imipenem-resistant isolates, including MDR (82.1%; 32/39), XDR (68.8%; 53/77) and difficult-to-treat (DTR) isolates (67.2%; 45/67). Among sequenced strains, differences in population structure were detected depending on the country: clonal complex (CC)175 and CC309 in Spain and CC235, CC244, CC348 and CC253 in Portugal. Different carbapenemase gene distributions were also found: VIM-20 (n = 3), VIM-1 (n = 2), VIM-2 (n = 1) and VIM-36 (n = 1) in Spain and GES-13 (n = 13), VIM-2 (n = 3) and KPC-3 (n = 2) in Portugal. GES-13-CC235 (n = 13) and VIM type-CC175 (n = 5) associations were predominant in Portugal and Spain, respectively. Imipenem/relebactam showed activity against KPC-3 strains (2/2), but was inactive against all GES-13 producers and most of the VIM producers (8/10). Mutations in genes affecting porin inactivation, efflux pump overexpression and LPS modification might also be involved in imipenem/relebactam resistance. CONCLUSIONS: Microbiological results reinforce imipenem/relebactam as a potential option to treat cUTI, cIAI and LRTI caused by MDR/XDR P. aeruginosa isolates, except for GES-13 and VIM producers.


Assuntos
Infecções por Pseudomonas , Infecções Respiratórias , Humanos , Pseudomonas aeruginosa/genética , Portugal , Infecções por Pseudomonas/microbiologia , Espanha , Compostos Azabicíclicos/farmacologia , Imipenem/farmacologia , Antibacterianos/farmacologia , Testes de Sensibilidade Microbiana , Unidades de Terapia Intensiva , Infecções Respiratórias/microbiologia
18.
Antimicrob Agents Chemother ; 66(9): e0078122, 2022 09 20.
Artigo em Inglês | MEDLINE | ID: mdl-36005804

RESUMO

Sulbactam-durlobactam is a ß-lactam-ß-lactamase inhibitor combination designed to treat serious Acinetobacter baumannii-calcoaceticus complex (ABC) infections, including carbapenem-non-susceptible and multidrug-resistant (MDR) isolates. The current study characterized the in vitro activity of sulbactam-durlobactam against a collection of 5,032 ABC clinical isolates collected in 33 countries across the Asia/South Pacific region, Europe, Latin America, the Middle East, and North America from 2016 to 2021. The sulbactam-durlobactam MIC50 and MIC90 were 1 and 2 µg/mL, respectively, for all ABC isolates tested. The addition of durlobactam (at a fixed concentration of 4 µg/mL) to sulbactam decreased its MIC50 by 8-fold (from 8 to 1 µg/mL) and its MIC90 by 32-fold (from 64 to 2 µg/mL) for all ABC isolates. The in vitro activity of sulbactam-durlobactam was maintained across individual ABC species, years, global regions of collection, specimen sources, and resistance phenotypes, including MDR and extensively drug-resistant (XDR) isolates. At 4 µg/mL (preliminary sulbactam-durlobactam susceptible MIC breakpoint), sulbactam-durlobactam inhibited 98.3% of all ABC isolates and >96% of sulbactam-, imipenem-, ciprofloxacin-, amikacin-, and minocycline-non-susceptible isolates; as well as colistin-resistant, MDR, and XDR isolates. Most imipenem-non-susceptible ABC isolates (96.8%, 2,488/2,570) were carbapenem-resistant A. baumannii (CRAB); 96.9% (2,410/2,488) of CRAB isolates were sulbactam-durlobactam-susceptible. More than 80% of ABC isolates had sulbactam-durlobactam MIC values that were ≥2 doubling-dilutions (4-fold) lower than sulbactam alone. Only 1.7% (84/5,032) of ABC isolates from 2016 to 2021 had sulbactam-durlobactam MIC values of >4 µg/mL. Of the 84 isolates, 94.0% were A. baumannii, 4.8% were A. pittii, and 1.2% were A. nosocomialis. In summary, sulbactam-durlobactam demonstrated potent antibacterial activity against a 2016 to 2021 collection of geographically diverse clinical isolates of ABC isolates, including carbapenem-non-susceptible and MDR isolates.


Assuntos
Infecções por Acinetobacter , Acinetobacter baumannii , Infecções por Acinetobacter/tratamento farmacológico , Infecções por Acinetobacter/microbiologia , Amicacina/uso terapêutico , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Compostos Azabicíclicos , Carbapenêmicos/farmacologia , Carbapenêmicos/uso terapêutico , Ciprofloxacina/uso terapêutico , Colistina/farmacologia , Combinação de Medicamentos , Humanos , Imipenem/farmacologia , Testes de Sensibilidade Microbiana , Minociclina/farmacologia , Sulbactam/farmacologia , Sulbactam/uso terapêutico , Inibidores de beta-Lactamases/farmacologia , Inibidores de beta-Lactamases/uso terapêutico
19.
Int J Antimicrob Agents ; 60(4): 106660, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35988666

RESUMO

Relebactam and vaborbactam are among the newest ß-lactamase inhibitors marketed. They were originally designed to inhibit the Ambler class A carbapenemase KPC. In this study, susceptibility to imipenem/relebactam and meropenem/vaborbactam was determined against a collection of OXA-48-like-producing Enterobacterales (n = 407). The clonality and resistomes of the isolates were determined by whole-genome sequencing. Comparison was performed with other relevant antibiotics such as carbapenems alone, ceftazidime/avibactam and ceftolozane/tazobactam. Addition of relebactam and vaborbactam did not significantly modify the MIC50 and MIC90 values obtained for imipenem and meropenem alone. In contrast, addition of avibactam strongly restored ceftazidime susceptibility. According to European Committee on Antimicrobial Susceptibility Testing (EUCAST) breakpoints, MIC50/MIC90 values were at 2/4, 2/4, 2/8, 2/8, 32/>32 and 0.5/2 mg/L for imipenem, imipenem/relebactam, meropenem, meropenem/vaborbactam, ceftazidime and ceftazidime/avibactam, respectively. No differences were observed depending on the species. This study highlights the lack of benefit in vitro for carbapenem/inhibitor combination compared with carbapenem alone against OXA-48-producing isolates as well as the difficulties in comparing molecules since carbapenem/inhibitor combinations were not developed with the same dosage of carbapenem.


Assuntos
Ceftazidima , Inibidores de beta-Lactamases , Antibacterianos/farmacologia , Compostos Azabicíclicos/farmacologia , Ácidos Borônicos , Carbapenêmicos/farmacologia , Ceftazidima/farmacologia , Combinação de Medicamentos , Imipenem/farmacologia , Meropeném/farmacologia , Testes de Sensibilidade Microbiana , Tazobactam , Inibidores de beta-Lactamases/farmacologia , beta-Lactamases/genética
20.
Microbiol Spectr ; 10(5): e0271021, 2022 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-35975993

RESUMO

The ongoing crisis of antimicrobial resistance demands novel combinations between antimicrobials and nonantimicrobials to manage infections caused by highly resistant pathogens. This study aimed to evaluate the effect of combining sodium ascorbate and/or apo-transferrin with imipenem, forming double and triple combinations, against 20 multiple-carbapenemase-producing Acinetobacter baumannii strains using the checkerboard test, time-kill assay, and disc diffusion test. The results of the checkerboard assay revealed that all double combinations showed indifference, while only triple combination recorded a synergistic effect (fractional inhibitory concentration index [FICI] < 0.8) in 95% the test isolates. Moreover, the MIC of imipenem (MICimp) was strongly reduced (up to 128-fold reduction) after treatment with the triple combination against highly resistant isolates and reached the susceptible range. The time-kill assay revealed that the triple combination led to a 4-log10 reduction in the CFU at 8 h compared with the initial bacterial count, and no viable count was recorded at 10 h. The mouse pneumonia model showed restoration of lung function and structure, with mild to moderate residual inflammation and moderately congested vessels observed 8 h following administration of the triple rescue therapy. Additionally, normal lungs with normal patent alveoli were detected 72 h following treatment. Accordingly, sodium ascorbate and apo-transferrin are promising adjunct biological agents with the potential to restore the effectiveness of critically essential antibiotics like imipenem, commonly used for the treatment of A. baumannii infections. IMPORTANCE Combination therapy provides a perspective to threat multidrug-resistant (MDR) strains. The present study sheds light on a novel and effective triple combination against carbapenem-resistant A. baumannii. Our in vitro results showed that combining imipenem with apo-transferrin and sodium ascorbate yielded synergism in 95% of test isolates, and this was associated with a marked reduction in imipenem MIC, shifting it below the breakpoint. Furthermore, a bactericidal effect was recorded, with no viable count detected at 10 h. An in vivo murine model of pneumonia was induced to mimic human disease. The triple combination therapy restored lung function and structure, with mild to moderate residual inflammation and moderately congested vessels observed 8 h following the initiation of therapy. Therefore, our findings suggest novel insights about a promising new combination therapy against highly resistant carbapenemase-producing A. baumannii to restore the effectiveness of imipenem.


Assuntos
Infecções por Acinetobacter , Acinetobacter baumannii , Pneumonia , Humanos , Camundongos , Animais , Infecções por Acinetobacter/tratamento farmacológico , Infecções por Acinetobacter/microbiologia , Modelos Animais de Doenças , Inosina Monofosfato/farmacologia , Testes de Sensibilidade Microbiana , Sinergismo Farmacológico , Imipenem/farmacologia , Imipenem/uso terapêutico , Carbapenêmicos/farmacologia , Carbapenêmicos/uso terapêutico , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Ácido Ascórbico/farmacologia , Ácido Ascórbico/uso terapêutico , Inflamação , Fatores Biológicos , Transferrinas/farmacologia , Farmacorresistência Bacteriana Múltipla
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