Cefoxitin 2g powder for solution for injection vials

ABSTRACT Guideline-based combination therapy achieves sputum culture conversion rates in 23%–34% of patients with Mycobacterium abscessus -complex lung disease. Thus, new therapies are needed. We performed a systematic review to validate and benchmark the hollow fiber system model of M. abscessus lung disease for drug development. We performed a literature search to identify all published hollow fiber system pharmacokinetic-pharmacodynamic studies. Preferred Reporting Items for Systematic Reviews and Meta-Analyses was used for bias minimization. A total of 12 studies were identified. The average quality score was 13.7 out of 21. Eight were monotherapy (exposure-effect and dose-fractionation), one double β-lactam, and three guideline-based therapy studies. For omadacycline and imipenem, hollow fiber system data were accompanied by clinical real-world evidence confirmation. Microbial kill was always terminated by antimicrobial resistance. We used quantitative analyses to rank drugs’ efficacy based on CFU/mL kill below day 0 bacterial burden normalized to multi-drug guideline-based therapy kill. The highest-ranked drugs were sulbactam-durlobactam-ceftriaxone (177-fold), epetraborole (15-fold), and omadacycline (7-fold) better than guideline-based therapy. We used the target exposures identified in the systematic analysis in Monte Carlo experiments to identify optimal doses for inhaled formulations. The optimal inhalational dose of imipenem was 250 mg/day, for tigecycline 4 mg/day, for cefoxitin 50 mg/day, and for amikacin liposome inhalation suspension 590 mg once weekly. The hollow fiber system model of M. abscessus lung disease is tractable for exposure-effect, dose-fractionation, and factorial design combination studies. It could also be used to rank drugs and inform on which drugs to test in novel combinations. IMPORTANCE Current treatments for Mycobacterium abscessus lung disease fail in 70%–80% of patients and are toxic. The hollow fiber system has been used to study old and new potential treatments for this disease. We performed a systematic review of this methodology, for lessons learned. We found 12 studies, which were of adequate quality. Efficacy was always terminated by antimicrobial resistance. The top three drugs in terms of efficacy were sulbactam-durlobactam-ceftriaxone, epetraborole, and omadacycline, which were 7 to 177 times better than standard of care. These drugs could be combined into a new treatment regimen better than current treatments. We also calculated new doses for imipenem, tigecycline, cefoxitin, and amikacin when administered as inhalational therapy. The inhaled doses were multiple-fold lower than intravenous ones, which could be less toxic. The hollow fiber system model is an easily managed system from drug development and dose finding for M. abscessus lung disease.

Abstract licence: CC BY

Therapies which target quorum sensing (QS) systems that regulate virulence in methicillin-resistant Staphylococcus aureus (MRSA) are a promising alternative to antibiotics. QS systems play a crucial in the regulation of MRSA antibiotic resistance, exotoxin production, antioxidant protection and immune cell evasion, and are therefore attractive therapeutic targets to reduce the virulence of a pathogen. In the present work the the effects of bioactive peptides isolated from two strains of lactic acid bacteria were tested against antibiotic resistance, carotenoid production, resistance to oxidative killing and biofilm structure in two clinical MRSA isolates. The results obtained from fractional-inhibitory concentration assays with bulk and semi-purified bioactive molecules showed a significant synergistic effect increasing cefoxitin mediated killing of MRSA. This was coupled to a six-fold decrease of the major membrane pigment staphyloxanthin, and a 99% increase in susceptibility to oxidative stress mediated killing. Real-time quantitative PCR analysis of the QS-genes agrA and luxS, showed differential expression between MRSA strains, and a significant downregulation of the hemolysin gene hla. Light microscopy and scanning electron microscopy revealed alteration in biofilm formation and clustering behavior. These results demonstrate that bioactive metabolites may be effectively applied in tandem with beta-lactam antibiotics to sensitize MRSA to cefoxitin. Moreover, these results shown that several key QS-controlled virulence mechanisms are diminished by probiotic metabolites.

Abstract licence: CC BY

ABSTRACT This study characterized cefoxitin-resistant and -susceptible Salmonella enterica serovar Heidelberg strains from humans, abattoir poultry, and retail poultry to assess the molecular relationships of isolates from these sources in Québec in 2012. Isolates were collected as part of the Canadian Integrated Program for Antimicrobial Resistance Surveillance (CIPARS). All isolates were subjected to antimicrobial susceptibility testing, PCR for CMY-2, pulsed-field gel electrophoresis (PFGE), and whole-genome sequencing (WGS). A total of 113 S . Heidelberg isolates from humans ( n = 51), abattoir poultry ( n = 18), and retail poultry ( n = 44) were studied. All cefoxitin-resistant isolates ( n = 65) were also resistant to amoxicillin-clavulanic acid, ampicillin, ceftiofur, and ceftriaxone, and all contained the CMY-2 gene. PFGE analysis showed that 111/113 (98.2%) isolates clustered together with ≥90% similarity. Core genome analysis using WGS identified 13 small clusters of isolates with 0 to 4 single nucleotide variations (SNVs), consisting of cefoxitin-resistant and -susceptible human, abattoir poultry, and retail poultry isolates. CMY-2 plasmids from cefoxitin-resistant isolates all belonged to incompatibility group I1. Analysis of IncI1 plasmid sequences revealed high identity (95 to 99%) to a previously described plasmid (pCVM29188_101) found in Salmonella Kentucky. When compared to pCVM29188_101, all sequenced cefoxitin-resistant isolates were found to carry 1 of 10 possible variant plasmids. Transmission of S . Heidelberg may be occurring between human, abattoir poultry, and retail poultry sources, and transmission of a common CMY-2 plasmid may be occurring among S . Heidelberg strains with variable genetic backgrounds.

Abstract licence: CC BY