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Microbiology Spectrum Dec 2023Newer antibiotics against Gram-negative pathogens provide important treatment options, especially for antibiotic-resistant bacteria, but little is known about their use...
Newer antibiotics against Gram-negative pathogens provide important treatment options, especially for antibiotic-resistant bacteria, but little is known about their use during routine clinical care. To use these agents appropriately, clinicians need to have access to timely susceptibility data. We evaluated 27,531 facility-reported susceptibility results from the BD Insights Research Database to gain a better understanding of real-world testing practices and susceptibility rates for six newer antibiotics. was the most frequently tested potential pathogen, and ceftazidime-avibactam and ceftolozane-tazobactam had the greatest numbers of susceptibility results. For cefiderocol, eravacycline, imipenem-relabactam, and meropenem-vaborbactam, susceptibility data were available for fewer than 2% of isolates. Susceptibility comparisons should be considered with caution. Ceftazidime-avibactam had the highest susceptibility rates for Enterobacterales while cefiderocol had the highest susceptibility rates for . New antibiotics have the potential to improve the management of Gram-negative infections, but their use may be hampered by the absence of susceptibility data.
Topics: Humans; Anti-Bacterial Agents; Pseudomonas aeruginosa; Carbapenems; Cephalosporins; Pseudomonas Infections; Cefiderocol; Microbial Sensitivity Tests
PubMed: 37937985
DOI: 10.1128/spectrum.03129-23 -
Microbiology Spectrum Apr 2024Carbapenem-resistant and spp. represent major threats and have few approved therapeutic options. Non-fermenting Gram-negative isolates were collected from...
UNLABELLED
Carbapenem-resistant and spp. represent major threats and have few approved therapeutic options. Non-fermenting Gram-negative isolates were collected from hospitalized inpatients from 49 sites in 6 European countries between 01 January 2020 and 31 December 2020 and underwent susceptibility testing against cefiderocol and β-lactam/β-lactamase inhibitor combinations. Meropenem-resistant (MIC >8 mg/L), cefiderocol-susceptible isolates were analyzed by PCR, and cefiderocol-resistant isolates were analyzed by whole-genome sequencing to identify resistance mechanisms. Overall, 1,451 (950 . ; 501 spp.) isolates were collected, commonly from the respiratory tract (42.0% and 39.3%, respectively). Cefiderocol susceptibility was higher than β-lactam/β-lactamase inhibitor combinations against (98.9% vs 83.3%-91.4%), and resistant to meropenem ( = 139; 97.8% vs 12.2%-59.7%), β-lactam/β-lactamase inhibitor combinations (93.6%-98.1% vs 10.7%-71.8%), and both meropenem and ceftazidime-avibactam (96.7% vs 5.0%-45.0%) or ceftolozane-tazobactam (98.4% vs 8.1%-54.8%), respectively. Cefiderocol and sulbactam-durlobactam susceptibilities were high against spp. (92.4% and 97.0%) and meropenem-resistant spp. ( = 227; 85.0% and 93.8%) but lower against sulbactam-durlobactam- ( = 15; 13.3%) and cefiderocol- ( = 38; 65.8%) resistant isolates, respectively. Among meropenem-resistant and spp., the most common β-lactamase genes were metallo-β-lactamases [30/139; (15/139)] and oxacillinases [215/227; (194/227)], respectively. Acquired β-lactamase genes were identified in 1/10 and 32/38 of cefiderocol-resistant and spp., and -like or mutations in 10/10 and 37/38, respectively. cefiderocol susceptibility was high against and spp., including meropenem-resistant isolates and those resistant to recent β-lactam/β-lactamase inhibitor combinations common in first-line treatment of European non-fermenters.
IMPORTANCE
This was the first study in which the activity of cefiderocol and non-licensed β-lactam/β-lactamase inhibitor combinations were directly compared against and spp., including meropenem- and β-lactam/β-lactamase inhibitor combination-resistant isolates. A notably large number of European isolates were collected. Meropenem resistance was defined according to the MIC breakpoint for high-dose meropenem, ensuring that data reflect antibiotic activity against isolates that would remain meropenem resistant in the clinic. Cefiderocol susceptibility was high against non-fermenters, and there was no apparent cross resistance between cefiderocol and β-lactam/β-lactamase inhibitor combinations, with the exception of sulbactam-durlobactam. These results provide insights into therapeutic options for infections due to resistant and spp. and indicate how early susceptibility testing of cefiderocol in parallel with β-lactam/β-lactamase inhibitor combinations will allow clinicians to choose the effective treatment(s) from all available options. This is particularly important as current treatment options against non-fermenters are limited.
Topics: Humans; Meropenem; Cefiderocol; beta-Lactamase Inhibitors; Pseudomonas aeruginosa; Lactams; Anti-Bacterial Agents; Cephalosporins; Pseudomonas Infections; Gram-Negative Bacteria; Acinetobacter; Microbial Sensitivity Tests; beta-Lactamases
PubMed: 38483164
DOI: 10.1128/spectrum.03836-23 -
China CDC Weekly Dec 2023Bacterial resistance surveillance is crucial for monitoring and understanding the trends and spread of drug-resistant bacteria.
WHAT IS ALREADY KNOWN ABOUT THIS TOPIC?
Bacterial resistance surveillance is crucial for monitoring and understanding the trends and spread of drug-resistant bacteria.
WHAT IS ADDED BY THIS REPORT?
The number of strains collected in 2022 increased compared to 2021. The top five bacteria, including , , , , and Acinetobacter baumannii, remained largely unchanged. The detection rate of methicillin-resistant strains continued to decrease. Among clinical isolates, the resistance rate to carbapenems was generally below 13%, except for spp., which had a resistance range of 20.4% to 21.9%. Most clinical isolates were highly susceptible to tigecycline, colistin, and polymyxin B, with resistance rates ranging from 0.1% to 12.6%. The detection rate of meropenem-resistant and meropenem-resistant showed a decreasing trend for the fourth consecutive year.
WHAT ARE THE IMPLICATIONS FOR PUBLIC HEALTH PRACTICE?
Multidrug-resistant bacteria remain a significant public health challenge in clinical antimicrobial treatment. To effectively address bacterial resistance, it is essential to enhance both bacterial resistance surveillance and the prudent use of antimicrobial agents.
PubMed: 38164466
DOI: 10.46234/ccdcw2023.217 -
Antibiotics (Basel, Switzerland) Dec 2023The rapid emergence of multi-drug resistant Gram-negative pathogens has driven the introduction of novel β-lactam combination agents (BLCs) to the antibiotic market:... (Review)
Review
The rapid emergence of multi-drug resistant Gram-negative pathogens has driven the introduction of novel β-lactam combination agents (BLCs) to the antibiotic market: ceftolozane-tazobactam, ceftazidime-avibactam, meropenem-vaborbactam, imipenem-relebactam, cefiderocol, and sulbactam-durlobactam. These agents are equipped with innovative mechanisms that confer broad Gram-negative activity, notably against certain challenging carbapenemases. While their introduction offers a beacon of hope, clinical microbiology laboratories must navigate the complexities of susceptibility testing for these agents due to their diverse activity profiles against specific β-lactamases and the possibility of acquired resistance mechanisms in some bacterial isolates. This review explores the complexities of these novel antimicrobial agents detailing the intricacies of their application, providing guidance on the nuances of susceptibility testing, interpretation, and result reporting in clinical microbiology laboratories.
PubMed: 38136734
DOI: 10.3390/antibiotics12121700 -
Frontiers in Pharmacology 2023The rate of carbapenem-resistant (CRKP) infection has been increasing rapidly worldwide and, poses a significant risk to human health. Effective methods are urgently...
The rate of carbapenem-resistant (CRKP) infection has been increasing rapidly worldwide and, poses a significant risk to human health. Effective methods are urgently needed to address treatment failures related to antibiotic resistance. Recent research has reported that some drugs in combination with antibiotics have displayed synergistic killing of resistant bacteria. Here, we investigated whether glutathione (GSH) can synergize with meropenem, and enhance its effectiveness against CRKP. Synergistic activity was assessed by checkerboard and time-killing assays. The mechanism of these combinations was assessed by total ROS and membrane permeability assays. The bacterial metabolites were assessed by LC‒MS/MS. The FICIs of GSH and meropenem were approximately 0.5 and the combined treatment with GSH and meropenem resulted in a more than 2log10 CFU/mL reduction in bacteria compared to the individual treatments. These findings indicated the synergistic effect of the two drugs. Moreover, the meropenem MIC of CRKP was reduced to less than 4 mg/L when combined with 6 mg/mL GSH, indicating that GSH could significantly reverse resistance to meropenem in bacteria. The production of ROS in bacteria was determined by flow cytometry. After adding GSH, the ROS in the GSH group and the combined group was significantly higher than that in the control and meropenem groups, but there was no significant difference between the combined and GSH groups. The metabolic disturbance caused by GSH alone and in combination with meropenem was significant intracellularly and extracellularly, especially in terms of glycerophospholipid metabolism, indicating that the synergistic effect of the combined use of GSH and meropenem was relevant to glycerophospholipid metabolism. In addition, we measured the cell membrane permeability. The cell membrane permeability of the combination group was significantly higher than that of the blank control or monotreatment groups. This confirmed that the GSH can serve as a meropenem enhancers by disturbing glycerophospholipid metabolism and increasing cell membrane permeability. GSH and meropenem display a synergistic effect, wherein GSH increases the sensitivity of CRKP to meropenem. The synergy and susceptibility effects are thought to related to the increased membrane permeability resulting from the perturbations in glycerophospholipid metabolism, presenting a novel avenue for CRKP treatment.
PubMed: 38174220
DOI: 10.3389/fphar.2023.1327230 -
The Pediatric Infectious Disease Journal Jul 2023Ceftolozane/tazobactam, a cephalosporin-β-lactamase inhibitor combination, is approved for the treatment of complicated urinary tract infections and complicated... (Randomized Controlled Trial)
Randomized Controlled Trial
Safety and Efficacy of Ceftolozane/Tazobactam Plus Metronidazole Versus Meropenem From a Phase 2, Randomized Clinical Trial in Pediatric Participants With Complicated Intra-abdominal Infection.
BACKGROUND
Ceftolozane/tazobactam, a cephalosporin-β-lactamase inhibitor combination, is approved for the treatment of complicated urinary tract infections and complicated intra-abdominal infections (cIAI). The safety and efficacy of ceftolozane/tazobactam in pediatric participants with cIAI were assessed.
METHODS
This phase 2 study (NCT03217136) randomized participants to either ceftolozane/tazobactam+metronidazole or meropenem for treatment of cIAI in pediatric participants (<18 years). The primary objective was to assess the safety and tolerability of intravenous ceftolozane/tazobactam+metronidazole. Clinical cure at end of treatment (EOT) and test of cure (TOC) visits were secondary end points.
RESULTS
The modified intent-to-treat (MITT) population included 91 participants (ceftolozane/tazobactam+metronidazole, n = 70; meropenem, n = 21). Complicated appendicitis was the most common diagnosis (93.4%); Escherichia coli was the most common pathogen (65.9%). Adverse events (AEs) occurred in 80.0% and 61.9% of participants receiving ceftolozane/tazobactam+metronidazole and meropenem, drug-related AEs occurred in 18.6% and 14.3% and serious AEs occurred in 11.4% and 0% of participants receiving ceftolozane/tazobactam+metronidazole and meropenem, respectively. No drug-related serious AEs or discontinuations due to drug-related AEs occurred. Rates of the clinical cure for ceftolozane/tazobactam+metronidazole and meropenem at EOT were 80.0% and 95.2% (difference: -14.3; 95% confidence interval: -26.67 to 4.93) and at TOC were 80.0% and 100.0% (difference: -19.1; 95% confidence interval: -30.18 to -2.89), respectively; 6 of the 14 clinical failures for ceftolozane/tazobactam+metronidazole at TOC were indeterminate responses imputed as failures per protocol.
CONCLUSION
Ceftolozane/tazobactam+metronidazole was well tolerated in pediatric participants with cIAI and had a safety profile similar to the established safety profile in adults. In this descriptive efficacy analysis, ceftolozane/tazobactam+metronidazole appeared efficacious.
Topics: Adult; Humans; Child; Meropenem; Metronidazole; Anti-Bacterial Agents; Penicillanic Acid; Cephalosporins; Tazobactam; Intraabdominal Infections; Escherichia coli
PubMed: 37000942
DOI: 10.1097/INF.0000000000003911 -
The Journal of Antimicrobial... Jul 2023To assess the global and regional distribution of ESBLs in Enterobacterales and carbapenemases in Enterobacterales and Pseudomonas aeruginosa.
OBJECTIVES
To assess the global and regional distribution of ESBLs in Enterobacterales and carbapenemases in Enterobacterales and Pseudomonas aeruginosa.
METHODS
Antimicrobial susceptibility of isolates collected from ATLAS (2017-2019) was determined per CLSI guidelines. Enterobacterales exhibiting meropenem MICs ≥2 mg/L and/or ceftazidime/avibactam and/or aztreonam/avibactam MICs ≥16 mg/L, Escherichia coli and Klebsiella pneumoniae with aztreonam and/or ceftazidime MICs ≥2 mg/L, and P. aeruginosa with meropenem MICs ≥4 mg/L were screened for β-lactamases by PCR and sequencing.
RESULTS
Globally, ESBL-positive E. coli (23.7%, 4750/20047) and K. pneumoniae (35.1%, 6055/17229) carried predominantly the CTX-M-15 variant (E. coli: 53.9%; K. pneumoniae: 80.0%) with highest incidence in Africa/Middle East (AfME). Among carbapenem-resistant (CR) E. coli (1.1%, 217/20047) and Enterobacter cloacae (3.8%, 259/6866), NDMs were predominant (E. coli in AfME: 62.5%; E. cloacae in Asia Pacific: 59.7%). CR K. pneumoniae (13.3%, 2299/17 229) and P. aeruginosa (20.3%, 4187/20 643) carried predominantly KPC (30.9%) and VIM (14.7%), respectively, with highest frequency in Latin America. Among ESBL-positive Enterobacterales, susceptibility to ceftazidime/avibactam (>90.0%) and amikacin (>85.0%) was higher than to piperacillin/tazobactam (>45.0%) and ciprofloxacin (>7.4%). In CR Enterobacterales, susceptibility to amikacin (>54.0%) and ceftazidime/avibactam (>31.0%) was higher than to ciprofloxacin (>2.7%) and piperacillin/tazobactam (>0.5%). CR P. aeruginosa similarly demonstrated higher susceptibility to amikacin (63.4%) and ceftazidime/avibactam (61.9%) than to ciprofloxacin (26.2%) and piperacillin/tazobactam (25.3%).
CONCLUSIONS
Varied distribution of resistance genotypes across regions among ESBL-positive Enterobacterales and CR Enterobacterales and P. aeruginosa provide crucial insights on major resistance mechanisms and trends observed in recent years. Continued surveillance is warranted for monitoring global dissemination and resistance.
Topics: Ceftazidime; Pseudomonas aeruginosa; Anti-Bacterial Agents; Amikacin; Aztreonam; Meropenem; Escherichia coli; Incidence; Azabicyclo Compounds; beta-Lactamases; Piperacillin, Tazobactam Drug Combination; Klebsiella pneumoniae; Drug Combinations; Ciprofloxacin; Microbial Sensitivity Tests
PubMed: 37161662
DOI: 10.1093/jac/dkad127 -
Antimicrobial Stewardship & Healthcare... 2023Physician characteristics may be correlated with medical treatment decisions and patient outcomes. This study examined the correlations between characteristics of...
OBJECTIVE
Physician characteristics may be correlated with medical treatment decisions and patient outcomes. This study examined the correlations between characteristics of infectious disease (ID) physicians and the use of the restricted antimicrobial meropenem.
DESIGN
This was a retrospective cohort study following 27 attending ID physicians for 5 years at a large academic medical center.
METHODS
All inpatient ID clinical encounters between 2013 and 2018 were assessed for physician and patient characteristics, including patient Charlson Comorbidity Index, patient sex, ID service seeing the patient, physician career stage, physician training location, and physician sex. Adjusted and unadjusted odds ratios were calculated for the receipt of meropenem on the same day as an ID clinical note.
RESULTS
Between 2013 and 2018, meropenem was administered on the same day as 9046 (11.1%) of 81,787 inpatient ID encounters. After adjustment for patient and practice-specific factors, physician career stage was associated with administration of meropenem. Patients seen by mid-career and late-career ID physicians were more likely to receive meropenem than those seen by early-career physicians (aOR 1.22 95% confidence interval [CI 1.13-1.31 and aOR 1.17 95% CI 1.10-1.25, respectively).
CONCLUSIONS
ID provider characteristics may help target future antimicrobial stewardship program interventions.
PubMed: 37534281
DOI: 10.1017/ash.2023.193 -
Molecules (Basel, Switzerland) Jun 2023Copper (Cu) is an essential trace metal and its concentration in body plasma is tightly regulated. An increase in Cu concentration in body fluids is observed in numerous... (Review)
Review
Copper (Cu) is an essential trace metal and its concentration in body plasma is tightly regulated. An increase in Cu concentration in body fluids is observed in numerous pathological conditions, including infections caused by microorganisms. Evidence shows that Cu ions can impact the activity of antibiotics by increasing efficiency or diminishing/neutralizing antibiotic activity, forming complexes which may lead to antibiotic structure degradation. Herein, we represent the evidence available on Cu-antibiotic interactions and their possible impact on antimicrobial therapy efficiency. So far, in vitro studies described interactions between Cu ions and the majority of antibiotics in clinical use: penicillins, cephalosporins, carbapenems, macrolides, aminoglycosides, tetracyclines, fluoroquinolones, isoniazid, metronidazole. In vitro-described degradation or lower antimicrobial activity of amoxicillin, ampicillin, cefaclor, ceftriaxone, and meropenem in the presence of Cu ions suggest caution when using prescribed antibiotics in patients with altered Cu levels. On the other hand, several Cu-dependent compounds with antibacterial activity including the drug-resistant bacteria were discovered, such as thiosemicarbazones, disulfiram, dithiocarbamates, 8-hydroxiquinoline, phenanthrolines, pyrithione. Having in mind that the development of new antibiotics is already marked as inadequate and does not meet global needs, the potential of Cu-antibiotic interactions to change the efficiency of antimicrobial therapy requires further investigation.
Topics: Humans; Copper; Anti-Bacterial Agents; Meropenem; Ampicillin; Ions
PubMed: 37446795
DOI: 10.3390/molecules28135133 -
Proteome Science Sep 2023Pseudomonas aeruginosa is well known for its intrinsic ability to resist a wide range of antibiotics, thus complicates treatment. Thus, understanding the response of the...
BACKGROUND
Pseudomonas aeruginosa is well known for its intrinsic ability to resist a wide range of antibiotics, thus complicates treatment. Thus, understanding the response of the pathogen to antibiotics is important for developing new therapies. In this study, proteomic response of P. aeruginosa to the commonly used anti-pseudomonas antibiotics, ceftazidime (Caz) and meropenem (Mem) was investigated.
METHODS
P. aeruginosa ATCC 9027, an antibiotic-susceptible strain, was exposed to sub-MIC values of antibiotics either Caz or Mem for 14 days to obtain E1 strains and then cultured in antibiotic-free environments for 10 days to obtain E2 strains. Proteomes of the initial and E1, E2 strains were identified and comparatively analyzed using isobaric tags for relative and absolute quantitation (iTRAQ) in cooperation with nano LC-MS/MS. Noted up and down-regulated proteins were confirmed with quantitative reverse transcriptase PCR (qRT-PCR).
RESULTS
Overall, 1039 and 1041 proteins were identified in Caz and Mem-exposed strains, respectively. Upon antibiotic exposure, there were 7-10% up-regulated (Caz: 71, Mem: 85) and down-regulated (Caz: 106, Mem: 69) proteins (1.5-fold change cut-off). For both Caz and Mem, the DEPs were primarily the ones involved in metabolic process, membrane, virulence, protein synthesis, and antibiotic resistance in which proteins involved in antibiotics resistance tended to be up-regulated while proteins involved in protein synthesis and metabolic process were down-regulated. Noted proteins included beta-lactamase AmpC which was up-regulated and OprD which was down-regulated in both the antibiotic-exposed strains. Besides, biofilm formation related proteins TssC1 and Hcp1 in Caz- exposed strains and the membrane/ periplasmic proteins Azu and PagL in Mem-exposed strains were found significantly down-regulated. qRT-PCR results confirmed the expression change of AmpC, Hcp1 and OprD proteins.
CONCLUSION
Exposure of Pseudomonas aeruginosa to sub-MIC values of Caz and Mem resulted in around 10% change in its proteome. Not only proteins with confirmed roles in antibiotic resistance mechanisms changed their expression but also virulence- associated proteins. Both Caz and Mem response involved up-regulation of AmpC and down-regulation of OprD. While TssC1 and Hcp1 were responsible for Caz response, Azu and PagL were more likely involved in Mem response.
PubMed: 37770917
DOI: 10.1186/s12953-023-00217-6