-
Antimicrobial Agents and Chemotherapy Jan 2024Cefiderocol is a siderophore cephalosporin designed to target multi-drug-resistant Gram-negative bacteria. Previously, the emergence of cefiderocol non-susceptibility...
Cefiderocol is a siderophore cephalosporin designed to target multi-drug-resistant Gram-negative bacteria. Previously, the emergence of cefiderocol non-susceptibility has been associated with mutations in the chromosomal cephalosporinase (PDC) along with mutations in the PirA and PiuA/D TonB-dependent receptor pathways. Here, we report a clinical case of cefiderocol-resistant that emerged in a patient during treatment. This resistance was associated with mutations not previously reported, suggesting potential novel pathways to cefiderocol resistance.
Topics: Humans; Anti-Bacterial Agents; Cefiderocol; Cephalosporins; Drug Resistance, Multiple, Bacterial; Gram-Negative Bacteria; Microbial Sensitivity Tests; Monobactams; Pseudomonas aeruginosa; Pseudomonas Infections
PubMed: 38063509
DOI: 10.1128/aac.01009-23 -
Current Microbiology Dec 2023Stenotrophomonas maltophilia is naturally resistant to many antimicrobials. We evaluated the in vitro activity and reproducibility of two different super-position...
Stenotrophomonas maltophilia is naturally resistant to many antimicrobials. We evaluated the in vitro activity and reproducibility of two different super-position methods of aztreonam in combination with ceftazidime-avibactam for S. maltophilia and compared these results with the recently available aztreonam-avibactam gradient strip. We recommend an improved super-position method that avoids the possible risk of handling a contaminated aztreonam strip. In addition, we report that the cefazidime-avibactam and aztreonam super-position method showed increased in vitro activity in comparison with aztreonam-avibactam indicating activity of the ceftazidime component in vitro.
Topics: Aztreonam; Ceftazidime; Anti-Bacterial Agents; Stenotrophomonas maltophilia; Reproducibility of Results; beta-Lactamases; Microbial Sensitivity Tests
PubMed: 38051338
DOI: 10.1007/s00284-023-03530-7 -
Antimicrobial Agents and Chemotherapy Dec 2023Cefiderocol is a siderophore cephalosporin that binds ferric iron and utilizes iron transporters to cross the cell membrane. Hypervirulent (hvKp) is known to produce...
Cefiderocol is a siderophore cephalosporin that binds ferric iron and utilizes iron transporters to cross the cell membrane. Hypervirulent (hvKp) is known to produce more siderophores; in this case, the uptake of cefiderocol may be decreased. Therefore, the objective of this study was to evaluate the activity of cefiderocol against hvKp isolates. A total of 320 carbapenem-resistant (CRKp) isolates were collected in China between 2014 and 2022, including 171 carbapenem-resistant hvKp (CR-hvKp) and 149 carbapenem-resistant classical (CR-cKp). Quantitative detection of siderophores showed that the average siderophore production of CR-hvKp (234.6 mg/L) was significantly higher than that of CR-cKp (68.9 mg/L, < 0.001). The overall cefiderocol resistance rate of CR-hvKp and CR-cKp was 5.8% (10/171) and 2.7% (4/149), respectively. The non-susceptible rates of both cefiderocol and siderophore production of CR-hvKp isolates were higher than those of CR-cKp in either NDM-1- or KPC-2-producing groups. The MIC90 and MIC50 for CR-hvKp and CR-cKp were 8 mg/L and 2 mg/L and 4 mg/L and 1 mg/L, respectively. The cumulative cefiderocol MIC distribution for CR-hvKp was significantly lower than that of CR-cKp isolates ( = 0.003). KL64 and KL47 consisted of 53.9% (83/154) and 75.7% (53/70) of the ST11 CR-hvKp and CR-cKp, respectively, and the former had significantly higher siderophore production. In summary, cefiderocol might be less effective against CR-hvKp compared with CR-cKp isolates, highlighting the need for caution regarding the prevalence of cefiderocol-resistant strains, particularly in CR-hvKp isolates.
Topics: Humans; Cephalosporins; Cefiderocol; Siderophores; Klebsiella pneumoniae; Klebsiella Infections; Carbapenems; Monobactams; China; Iron; Carbapenem-Resistant Enterobacteriaceae; Anti-Bacterial Agents
PubMed: 38014944
DOI: 10.1128/aac.00735-23 -
The Journal of Antimicrobial... Jan 2024Antimicrobial activity of antibiotics can be impacted by pH, enhancing or reducing their bactericidal properties. Cefiderocol, a novel cephalosporin antibiotic that is...
BACKGROUND
Antimicrobial activity of antibiotics can be impacted by pH, enhancing or reducing their bactericidal properties. Cefiderocol, a novel cephalosporin antibiotic that is among others indicated for the treatment of complicated urinary tract infections (cUTIs), lacks data on activity in urine.
METHODS
Pooled human urine (iron levels ∼0.05 mg/L/24 h), CAMHB and iron-depleted CAMHB (ID-CAMHB) at pH 5, 7 and 8 served as media. MIC testing was done according to EUCAST with the broth microdilution method for 17 clinical isolates of Escherichia coli and ATCC 25922 (including isolates with ESBL activity), 17 clinical isolates of Klebsiella pneumoniae and ATCC 700603 (also with ESBL), and 6 clinical isolates of Pseudomonas aeruginosa and ATCC 27853. Time-kill curves (TKCs) were performed for selected strains at pH 5, 7 and 8 in urine.
RESULTS
MIC values in urine, CAMHB and ID-CAMHB exhibited isolate-specific variations when assessed under identical pH conditions, ranging from a 1-fold dilution to changes of up to 4-fold dilutions in either direction. Median MICs of cefiderocol were up to 50-fold higher in pH 5 than in pH 7 for P. aeruginosa isolates and 32-fold higher in E. coli and K. pneumoniae isolates. TKCs with 650 and 1300 mg/L cefiderocol in urine showed that ATCC strains were efficiently eradicated despite the pH set.
CONCLUSIONS
Acidic pH had a significant negative impact on cefiderocol activity. Yet, after a recommended IV administration of 2 g cefiderocol every 8 h, a concentration of approximately 1300 mg/L can be achieved in urine, suggesting that efficient killing of all tested pathogens could have been possible even under acidic conditions in vivo.
Topics: Humans; Cefiderocol; Cephalosporins; Escherichia coli; Anti-Bacterial Agents; Monobactams; Iron; Pseudomonas aeruginosa; Klebsiella pneumoniae; Hydrogen-Ion Concentration; Microbial Sensitivity Tests
PubMed: 38000090
DOI: 10.1093/jac/dkad361 -
Antibiotics (Basel, Switzerland) Nov 2023Medicinal plants with multiple targets of action have become one of the most promising solutions in the fight against multidrug-resistant (MDR) bacterial infections....
Medicinal plants with multiple targets of action have become one of the most promising solutions in the fight against multidrug-resistant (MDR) bacterial infections. (Tansy) is one of the medicinal plants with antibacterial qualities that deserve to be studied. Thus, this research takes a closer look at tansy extract's composition and antibacterial properties, aiming to highlight its potential against clinically relevant bacterial strains. In this respect, the antibacterial test was performed against several drug-resistant pathogenic strains, and we correlated them with the main isolated compounds, demonstrating the therapeutic properties of the extract. The essential oil was extracted via hydrodistillation, and its composition was characterized via gas chromatography. The main isolated compounds known for their antibacterial effects were α-Thujone, β-Thujone, Eucalyptol, Sabinene, Chrysanthenon, Camphor, Linalool oxide acetate, -Carveol, -Carveyl acetate, and Germacrene. The evaluation of the antibacterial activity was carried out using the Kirby-Bauer and binary microdilution methods on Gram-positive and Gram-negative MDR strains belonging to the ESKAPE group (i.e., , , , , , and spp.). Tansy essential oil showed MIC values ranging from 62.5 to 500 μg/mL against the tested strains. Synergistic activity with different classes of antibiotics (penicillins, cephalosporins, carbapenems, monobactams, aminoglycosides, and quinolones) has also been noted. The obtained results demonstrate that tansy essential oil represents a promising lead for developing new antimicrobials active against MDR alone or in combination with antibiotics.
PubMed: 37998837
DOI: 10.3390/antibiotics12111635 -
Journal of Medical Microbiology Nov 2023Lack of laboratory capacity hampers consistent national antimicrobial resistance (AMR) surveillance. Chromogenic media may provide a practical screening tool for...
Lack of laboratory capacity hampers consistent national antimicrobial resistance (AMR) surveillance. Chromogenic media may provide a practical screening tool for detection of individuals colonized by extended-spectrum beta-lactamase (ESBL)-producing organisms. CHROMagar ESBL media represent an adequate screening method for the detection of extended-spectrum cephalosporin-resistant (ESCrE), isolated from rectal swabs. To evaluate the performance of CHROMagar ESBL media to accurately identify ESCrE isolates from rectal swab samples attained from hospitalized and community participants. All participants provided informed consent prior to enrolment. Rectal swabs from 2469 hospital and community participants were inoculated onto CHROMagar ESBL. The performance of CHROMagar ESBL to differentiate and spp., spp. and spp. (KEC spp.) as well as select for extended-spectrum cephalosporin resistance were compared to matrix-assisted laser desorption/ionization-time-of-flight MS (MALDI-TOF-MS) and VITEK-2 automated susceptibility testing. CHROMagar ESBL had a positive and negative agreement of 91.2 % (95 % CI, 88.4-93.3) and 86.8 % (95 % CI, 82.0-90.7) for and 88.1 % (95 % CI 83.2-92.1) and 87.6 % (95 % CI 84.7-90.2) for KEC spp. differentiation, respectively, when compared to species ID by MALDI-TOF-MS. When evaluated for phenotypic susceptibilities (VITEK-2), 88.1 % (714/810) of the isolates recovered on the selective agar exhibited resistance to third-generation cephalosporins. The performance characteristics of CHROMagar ESBL media suggest that they may be a viable screening tool for the identification of ESCrE from hospitalized and community participants and could be used to inform infection prevention and control practices in Botswana and potentially other low-and middle-income countries (LMICs). Further studies are required to analyse the costs and the impact on time-to-result of the media in comparison with available laboratory methods for ESCrE surveillance in the country.
Topics: Humans; Cephalosporins; Botswana; Escherichia coli; Monobactams; Agar; Gammaproteobacteria; Hydrolases
PubMed: 37991431
DOI: 10.1099/jmm.0.001770 -
Microbiology Spectrum Dec 2023To our knowledge, this is the first study to report the activity of two novel antimicrobial drugs, including imipenem-relebactam (IMR) and aztreonam-avibactam (AZA),...
To our knowledge, this is the first study to report the activity of two novel antimicrobial drugs, including imipenem-relebactam (IMR) and aztreonam-avibactam (AZA), toward carbapenem-resistant and hypervirulent (CR-hvKP) strains. Our activity study revealed that only few antibacterial agents (including several novel agents) exhibit high antimicrobial activity toward carbapenem-resistant (CRKP) and CR-hvKP isolates. IMR and AZA may be promising therapeutic agents for the treatment of infections caused by CRKP and CR-hvKP isolates.
Topics: Humans; Aztreonam; Klebsiella pneumoniae; Bacterial Proteins; beta-Lactamases; Anti-Bacterial Agents; Carbapenem-Resistant Enterobacteriaceae; Imipenem; Carbapenems; Klebsiella Infections; Microbial Sensitivity Tests
PubMed: 37982631
DOI: 10.1128/spectrum.02806-23 -
Antimicrobial Agents and Chemotherapy Dec 2023is the most prevalent cystic fibrosis (CF) pathogen. Several phenotypes are associated with worsened CF clinical outcomes including methicillin-resistance and...
is the most prevalent cystic fibrosis (CF) pathogen. Several phenotypes are associated with worsened CF clinical outcomes including methicillin-resistance and small-colony-variants. The inoculum effect (IE) is characterized by reduced β-lactam susceptibility when assessed at high inoculum. The IE associates with worse outcomes in bacteremia and other high-density infections, and may therefore be relevant to CF. The prevalence of IE amongst a CF cohort (age ≥18 years), followed from 2013 to 2016, was investigated. Yearly methicillin-sensitive (MSSA) isolates were screened at standard (5 × 10 CFU/mL) and high (5 × 10 CFU/mL) inoculum against narrow-spectrum anti-Staphylococcal β-lactams and those with anti-pseudomonal activity common to CF. A ≥ 4-fold increase in minimum inhibitory concentration between standard and high inoculum defined IE. Isolates underwent sequencing and genotyping and were compared against published genomes. Fifty-six percent (99/177) of individuals had MSSA infection. MSSA was observed at ≥10 CFU/mL in 44.8% of entry sputum samples. The prevalence of the IE was 25.0%-cefazolin; 13.5%-cloxacillin; 0%-meropenem; 1.0%-cefepime; 5.2%-ceftazidime; and 34.4%-piperacillin-tazobactam amongst baseline MSSA isolates assessed. A associated with cefazolin IE ( = 0.0011), whereas C associated with piperacillin-tazobactam IE ( < 0.0001). Baseline demographics did not reveal specific risk factors for IE-associated infections, nor were long-term outcomes different. Herein, we observed the IE in CF-derived MSSA disproportionally for cefazolin and piperacillin-tazobactam and this phenotype strongly associated with underlying genotype. The confirmation of CF being a high density infection, and the identification of high prevalence of MSSA with IE in CF supports the need for prospective pulmonary exacerbation treatment studies to understand the impact of this phenotype.
Topics: Adult; Humans; Adolescent; Methicillin; Cefazolin; Staphylococcus aureus; Anti-Bacterial Agents; Prospective Studies; Cystic Fibrosis; Staphylococcal Infections; Monobactams; Piperacillin, Tazobactam Drug Combination; Ceftazidime; beta Lactam Antibiotics; Microbial Sensitivity Tests
PubMed: 37966229
DOI: 10.1128/aac.00136-23 -
Journal of Infection and Public Health Dec 2023Cefiderocol (CFDC) is a novel siderophore-cephalosporin, which usually penetrates the bacteria through the iron-uptake pathways. Data is limited on the factors affecting...
High efficacy and enhanced synergistic activity of the novel siderophore-cephalosporin cefiderocol against multidrug-resistant and extensively drug-resistant Klebsiella pneumoniae from inpatients attending a single hospital in the United Arab Emirates.
BACKGROUND
Cefiderocol (CFDC) is a novel siderophore-cephalosporin, which usually penetrates the bacteria through the iron-uptake pathways. Data is limited on the factors affecting CFDC activity and methods for overcoming resistance development. Synergistic approaches are needed to tackle antimicrobial resistance. This study aimed to determine CFDC activity on Klebsiella pneumoniae isolates from patients attending a single hospital in the United Arab Emirates (UAE), to explore the effect of β-lactamases on CFDC activity and to enhance CFDC susceptibility in both iron-depleted and iron-enriched conditions.
METHODS
We investigated 238 K. pneumoniae strains from diverse clinical sources. β-lactamase genes were detected by PCR. Susceptibility to CFDC and 12 comparator antibiotics were tested. Combinations of CFDC with β-lactamase inhibitors (BLIs) and/or an outer membrane (OM) permeabilizer (polymyxin B nonapeptide) were tested in iron-depleted and iron-enriched conditions.
RESULTS
CFDC exhibited efficacy of 97.9%, against multidrug-resistant (MDR), and extensively drug-resistant (XDR) strains, in addition to strains resistant to the last resort drugs such as colistin and tigecycline, including dual carbapenemase-producers (bla and bla) with MIC ≤ 0.06-8 µg/ml. It was effective in killing strains with single and multiple β-lactamases; however, it lost activity in iron-enriched conditions. Synergy was achieved with dual combination of CFDC and BLIs, especially avibactam, which caused a significant reduction in MICs even in iron-enriched conditions. A significant reduction was seen with the triple combination including an OM permeabilizer plus avibactam. Killing-kinetic studies proved that the combination therapy caused dose reduction and faster killing by CFDC than the monotherapy.
CONCLUSIONS
CFDC was deemed effective against MDR and XDR K. pneumoniae. Synergistic combination of CFDC with BLIs and OM permeabilizers could be effective to treat infections in iron-rich sites, but this should be investigated in vivo.
Topics: Humans; Siderophores; Klebsiella pneumoniae; Inpatients; United Arab Emirates; Kinetics; Anti-Bacterial Agents; Cephalosporins; beta-Lactamases; Monobactams; Iron; Hospitals; Microbial Sensitivity Tests; Cefiderocol
PubMed: 37953111
DOI: 10.1016/j.jiph.2023.11.003 -
Molecules (Basel, Switzerland) Oct 2023is a common human pathogen. Methicillin-resistant (MRSA) infections pose significant and challenging therapeutic difficulties. MRSA often acquires the non-native gene... (Review)
Review
is a common human pathogen. Methicillin-resistant (MRSA) infections pose significant and challenging therapeutic difficulties. MRSA often acquires the non-native gene PBP2a, which results in reduced susceptibility to β-lactam antibiotics, thus conferring resistance. PBP2a has a lower affinity for methicillin, allowing bacteria to maintain peptidoglycan biosynthesis, a core component of the bacterial cell wall. Consequently, even in the presence of methicillin or other antibiotics, bacteria can develop resistance. Due to genes responsible for resistance, becomes MRSA. The fundamental premise of this resistance mechanism is well-understood. Given the therapeutic concerns posed by resistant microorganisms, there is a legitimate demand for novel antibiotics. This review primarily focuses on PBP2a scaffolds and the various screening approaches used to identify PBP2a inhibitors. The following classes of compounds and their biological activities are discussed: Penicillin, Cephalosporins, Pyrazole-Benzimidazole-based derivatives, Oxadiazole-containing derivatives, non-β-lactam allosteric inhibitors, 4-(3)-Quinazolinones, Pyrrolylated chalcone, Bis-2-Oxoazetidinyl macrocycles (β-lactam antibiotics with 1,3-Bridges), Macrocycle-embedded β-lactams as novel inhibitors, Pyridine-Coupled Pyrimidinones, novel Naphthalimide corbelled aminothiazoximes, non-covalent inhibitors, Investigational-β-lactam antibiotics, Carbapenem, novel Benzoxazole derivatives, Pyrazolylpyridine analogues, and other miscellaneous classes of scaffolds for PBP2a. Additionally, we discuss the penicillin-binding protein, a crucial target in the MRSA cell wall. Various aspects of PBP2a, bacterial cell walls, peptidoglycans, different crystal structures of PBP2a, synthetic routes for PBP2a inhibitors, and future perspectives on MRSA inhibitors are also explored.
Topics: Humans; Penicillin-Binding Proteins; Methicillin-Resistant Staphylococcus aureus; Methicillin; Staphylococcus aureus; Anti-Bacterial Agents; Monobactams; Bacterial Proteins; Microbial Sensitivity Tests
PubMed: 37894491
DOI: 10.3390/molecules28207008