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Journal of Controlled Release :... Dec 2023Bacteriophage (phage) therapy has shown promise in treating fracture-related infection (FRI); however, questions remain regarding phage efficacy against biofilms,...
Bacteriophage (phage) therapy has shown promise in treating fracture-related infection (FRI); however, questions remain regarding phage efficacy against biofilms, phage-antibiotic interaction, administration routes and dosing, and the development of phage resistance. The goal of this study was to develop a dual antibiotic-phage delivery system containing hydrogel and alginate microbeads loaded with a phage cocktail plus meropenem and evaluate efficacy against muti-drug resistant Pseudomonas aeruginosa. Two phages (FJK.R9-30 and MK.R3-15) displayed enhanced antibiotic activity against P. aeruginosa biofilms when tested in combination with meropenem. The antimicrobial activity of both antibiotic and phage was retained for eight days at 37 °C in dual phage and antibiotic loaded hydrogel with microbeads (PA-HM). In a mouse FRI model, phages were recovered from all tissues within all treatment groups receiving dual PA-HM. Moreover, animals that received the dual PA-HM either with or without systemic antibiotics had less incidence of phage resistance and less serum neutralization compared to phages in saline. The dual PA-HM could reduce bacterial load in soft tissue when combined with systemic antibiotics, although the infection was not eradicated. The use of alginate microbeads and injectable hydrogel for controlled release of phages and antibiotics, leads to the reduced development of phage resistance and lower exposure to the adaptive immune system, which highlights the translational potential of the dual PA-HM. However, further optimization of phage therapy and its delivery system is necessary to achieve higher bacterial killing activity in vivo in the future.
Topics: Animals; Mice; Bacteriophages; Pseudomonas aeruginosa; Meropenem; Alginates; Microspheres; Pseudomonas Infections; Anti-Bacterial Agents; Biofilms
PubMed: 37866403
DOI: 10.1016/j.jconrel.2023.10.029 -
Revista Espanola de Quimioterapia :... Apr 2022The appearance and spread of new mechanisms of bacterial resistance to antibiotics is a serious health problem. One of the most difficult resistance mechanisms to treat... (Review)
Review
The appearance and spread of new mechanisms of bacterial resistance to antibiotics is a serious health problem. One of the most difficult resistance mechanisms to treat is the production of carbapenemases. Carbapenemase KPC is one of those mechanisms with few therapeutic options. Meropenem-vaborbactam has shown great efficacy against this type of microorganism, both from a clinical and microbiological point of view. Its good pharmacokinetics, including in the lung, and its safety profile make meropenem-vaborbactam an excellent therapeutic option. Finally, the absence of resistance genesis during treatment seems to indicate that its efficacy will be long-lasting.
Topics: Anti-Bacterial Agents; Boronic Acids; Humans; Meropenem; Pneumonia
PubMed: 35488825
DOI: 10.37201/req/s01.10.2022 -
International Journal of Antimicrobial... Dec 2023Meropenem in combination with β-lactamase inhibitors (BLIs) and other drugs was tested to identify alternative treatment regimens for multidrug-resistant tuberculosis...
BACKGROUND
Meropenem in combination with β-lactamase inhibitors (BLIs) and other drugs was tested to identify alternative treatment regimens for multidrug-resistant tuberculosis (MDR-TB).
METHODS
The following were performed: (1) MIC experiments; (2) static time-kill studies (STKs) with different BLIs; and (3) a hollow fibre model system of TB (HFS-TB) studies with meropenem-vaborbactam combined with human equivalent daily doses of 20 mg/kg or 35 mg/kg rifampin, or moxifloxacin 400 mg, or linezolid 600 mg vs. bedaquiline-pretonamid-linezolid (BPaL) for MDR-TB. The studies were performed using Mycobacterium tuberculosis (M. tuberculosis) H37Rv and an MDR-TB clinical strain (named M. tuberculosis 16D) that underwent whole genome sequencing. Exponential decline models were used to calculate the kill rate constant (K) of different HFS-TB regimens.
RESULTS
Whole genome sequencing revealed mutations associated with resistance to rifampin, isoniazid, and cephalosporins. The meropenem-vaborbactam MIC of M. tuberculosis was H37Rv 2 mg/L and > 128 mg/L for M. tuberculosis 16D. Relebactam and vaborbactam improved both the potency and efficacy of meropenem in STKs. Meropenem-vaborbactam alone failed to kill M. tuberculosis 16D but killed below day 0 burden when combined with isoniazid and rifampin, with the moxifloxacin combination being the most effective and outranking bedaquiline and pretomanid. In the HFS-TB, meropenem-vaborbactam-moxifloxacin and BPaL had the highest K (log cfu/mL/day) of 0.31 (95% CI 0.17-0.58) and 0.34 (95% CI 0.21-0.56), while meropenem-vaborbactam-rifampin (35 mg/kg) had a K of 0.18 (95% CI 0.12-0.25). The K for meropenem-vaborbactam-moxifloxacin-linezolid demonstrated antagonism.
CONCLUSION
Adding meropenem-vaborbactam could potentially restore the efficacy of isoniazid and rifampin against MDR-TB. The meropenem-vaborbactam-moxifloxacin backbone regimen has implications for creating a new effective MDR-TB regimen.
Topics: Humans; Moxifloxacin; Linezolid; Meropenem; Antitubercular Agents; Rifampin; Isoniazid; Tuberculosis, Multidrug-Resistant; Mycobacterium tuberculosis; beta-Lactamase Inhibitors
PubMed: 37726063
DOI: 10.1016/j.ijantimicag.2023.106968 -
The New Microbiologica Sep 2023Carbapenemase-producing Enterobacteriaceae (CPE) are an increasing threat to global public health. Treatment of CPE isolates, like New Delhi metallo-β-lactamase (NDM),...
Carbapenemase-producing Enterobacteriaceae (CPE) are an increasing threat to global public health. Treatment of CPE isolates, like New Delhi metallo-β-lactamase (NDM), is limited and often necessitates combination therapies. The aim of this study was to evaluate the synergistic meropenem/fosfomycin combination against K.pneumoniae-producing NDM isolates. Fosfomycin/meropenem, fosfomycin/colistin and meropenem/colistin were tested alone and in combination, using e-test and time-kill assay against 20 clinical carbapenemase-producing K. pneumonia (CPKp NDM) isolates collected from September 2022 to December 2022. K. pneumoniae strains were resistant to meropenem, ceftazidime/avibactam and ceftolozano/tazobactam, 75% and 80% of isolates were susceptible for cefiderocol and for colistin respectively. Fosfomycin/meropenem combination was synergic in 95% (n=19) strains. Fosfomycin/colistin and colistin/meropenem combination showed only 10% synergistic combination strains. In 16 isolates (80%) indifference action for fosfomycin/colistin and colistin/meropenem was reported. For 0.8% of CpKP NDM isolates colistin/meropenem and fosfomycin/colistin combinations found to be antagonistic. In this study, time kill assay showed combination therapies action versus K.pneumoniae metallo-b-lactamase producing (NDM) strains and confirmed the synergistic action of fosfomycin/meropenem combination. In vitro synergy testing should be routinely performed in multidrug resistance infections and combo therapies can be used as a possible alternative in targeted patients with the goal of reducing overall antibiotic costs.
Topics: Humans; Meropenem; Fosfomycin; Colistin; Klebsiella pneumoniae; Carbapenem-Resistant Enterobacteriaceae
PubMed: 37747471
DOI: No ID Found -
Current Drug Metabolism Aug 2022Meropenem is a carbapenem antibiotic and is commonly used with other antibiotics for the treatment of bacterial infections. It is primarily eliminated renally by...
BACKGROUND
Meropenem is a carbapenem antibiotic and is commonly used with other antibiotics for the treatment of bacterial infections. It is primarily eliminated renally by glomerular filtration and renal tubular secretion.
OBJECTIVE
This study aimed to evaluate the roles of renal uptake and efflux transporters in the excretion of meropenem and potential drug interactions mediated by renal drug transporters.
METHODS
Uptake and inhibition studies were conducted in human embryonic kidney 293 cells stably transfected with Organic Anion Transporter (OAT) 1, OAT3, Multidrug and Toxin Extrusion Protein (MATE) 1, and MATE2K, as well as membrane vesicles containing breast cancer resistance-related protein (BCRP), multidrug resistance protein 1 (MDR1), and Multidrug Resistance-associated Protein 2 (MRP2). Probenecid and piperacillin were used to assess potential drug interactions with meropenem in rats.
RESULTS
We observed that meropenem was a low-affinity substrate of OAT1/3 and had a weak inhibitory effect on OAT1/3 and MATE2K. BCRP, MDR1, MRP2, MATE1, and MATE2K could not mediate renal excretion of meropenem. Moreover, meropenem was not an inhibitor of BCRP, MDR1, MRP2, or MATE1. Among five tested antibiotics, moderate inhibition on OAT3-mediated meropenem uptake was observed for linezolid (IC value was 69.2 μM), weak inhibition was observed for piperacillin, benzylpenicillin, and tazobactam (IC values were 282.2, 308.0 and 668.1 μM, respectively), and no inhibition was observed for sulbactam. Although piperacillin had a relatively high drug-drug interaction index (ratio of maximal unbound plasma concentration to IC was 1.42) in vitro, no meaningful impact was reported on the pharmacokinetics of meropenem in rats.
CONCLUSION
Our results indicated that clinically significant interactions between meropenem and these five antibiotics are low.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; ATP Binding Cassette Transporter, Subfamily G, Member 2; Animals; Anti-Bacterial Agents; Drug Interactions; Humans; Kidney; Membrane Transport Proteins; Meropenem; Neoplasm Proteins; Organic Anion Transporters; Organic Anion Transporters, Sodium-Independent; Piperacillin; Rats
PubMed: 35490314
DOI: 10.2174/1389200223666220428081109 -
Drug Discovery Today Feb 2021An increase in the number of multidrug-resistant microbial strains is the biggest threat to global health and is projected to cause >10 million deaths by 2055. The... (Review)
Review
An increase in the number of multidrug-resistant microbial strains is the biggest threat to global health and is projected to cause >10 million deaths by 2055. The carbapenem family of antibacterial drugs are an important class of last-resort treatment of infections caused by drug-resistant bacteria and are only available as an injectable formulation. Given their instability within the gut and poor permeability across the gut wall, oral carbapenem formulations show poor bioavailability. Meropenem (MER), a carbapenem antibiotic, has broad-spectrum antibacterial activity, but suffers from the above-mentioned issues. In this review, we discuss strategies for improving the oral bioavailability of MER, such as inhibiting tubular secretion, prodrug formulations, and use of nanomedicine. We also highlight challenges and emerging approaches for the development of oral MER.
Topics: Administration, Oral; Animals; Anti-Bacterial Agents; Bacterial Infections; Biological Availability; Drug Development; Drug Resistance, Multiple, Bacterial; Global Health; Humans; Meropenem
PubMed: 33197621
DOI: 10.1016/j.drudis.2020.11.004 -
Antimicrobial Agents and Chemotherapy Jan 2020The most common mechanism of resistance to β-lactams antibiotics in Gram-negative bacteria is production of β-lactamase enzymes capable of cleaving the β-lactam ring....
The most common mechanism of resistance to β-lactams antibiotics in Gram-negative bacteria is production of β-lactamase enzymes capable of cleaving the β-lactam ring. Inhibition of β-lactamase activity with small-molecule drugs is a proven strategy to restore the potency of many β-lactam antibiotics. Vaborbactam (formerly RPX7009) is a cyclic boronic acid β-lactamase inhibitor (BLI) with a broad spectrum of activity against various serine β-lactamases, including KPC carbapenemases. The combination of vaborbactam and meropenem is approved in the United States and Europe for the treatment of various nosocomial infections. We attempted to gain more insight into the mechanism of action of vaborbactam by conducting detailed kinetic characterization of its interaction with various recombinant His-tagged β-lactamases. Vaborbactam demonstrated potent inhibition of class A and class C enzymes with values ranging from 0.022 to 0.18 μM, while inhibition of class D enzymes was rather poor, and no activity against class B β-lactamases was detected. Importantly, vaborbactam inhibited KPC-2, KPC-3, BKC-1, and SME-2 carbapenemases at 1:1 stoichiometry, while these numbers were higher for other class A and C enzymes. Vaborbactam was also shown to be a potent progressive inactivator of several enzymes, including KPCs with inactivation constants / in the range of 3.4 × 10 to 2.4 × 10 M s Finally, experiments on the recovery of enzyme activity demonstrated the high stability of the vaborbactam-KPC complex, with 0.000040 s values and a corresponding residence time of 7 h, whereas the release of vaborbactam bound to other serine β-lactamases was substantially faster. The biochemical characteristics of vaborbactam described in this study may facilitate further chemical optimization efforts to develop boronic BLIs with improved affinity and broader spectrum of inhibition.
Topics: Anti-Bacterial Agents; Bacterial Proteins; Boronic Acids; Heterocyclic Compounds, 1-Ring; Meropenem; Microbial Sensitivity Tests; beta-Lactamase Inhibitors; beta-Lactamases
PubMed: 31712199
DOI: 10.1128/AAC.01935-19 -
The Journal of Antimicrobial... Dec 2023Antimicrobial resistance in Pseudomonas aeruginosa is complex and multifaceted. While the novel β-lactamase inhibitors (BLIs) avibactam, relebactam and vaborbactam...
BACKGROUND
Antimicrobial resistance in Pseudomonas aeruginosa is complex and multifaceted. While the novel β-lactamase inhibitors (BLIs) avibactam, relebactam and vaborbactam inhibit serine-based β-lactamases, the comparative potency of the novel β-lactam (BL)/BLI combinations against serine carbapenemase-producing P. aeruginosa is unknown.
OBJECTIVES
To compare the in vitro activity of ceftazidime/avibactam, ceftazidime, imipenem/relebactam, imipenem, meropenem/vaborbactam and meropenem against serine β-lactamase-producing P. aeruginosa.
METHODS
Carbapenem-resistant P. aeruginosa were collated through the Enhancing Rational Antimicrobials against Carbapenem-resistant P. aeruginosa (ERACE-PA) Global Surveillance. Isolates positive for serine-based carbapenemases were assessed. MICs were determined by broth microdilution to each novel BL/BLI and BL alone.
RESULTS
GES was the most common carbapenemase identified (n = 59) followed by KPC (n = 8). Ceftazidime/avibactam had MIC50/MIC90 values of 4/8 mg/L and 91% of isolates were susceptible. Conversely, ceftazidime alone was active against only 3% of isolates. The MIC50/MIC90 of imipenem/relebactam were 16/>16 mg/L and 13% of all isolates were defined as susceptible. Of the KPC-producing isolates, 38% were susceptible to imipenem/relebactam, compared with 0% to imipenem. The meropenem/vaborbactam MIC50/MIC90 were >16/>16 mg/L, and 6% of isolates were susceptible, which was similar to meropenem alone (MIC50/90, >8/>8 mg/L; 3% susceptible) suggesting the addition of vaborbactam cannot overcome co-expressed, non-enzymatic resistance mechanisms.
CONCLUSIONS
Among the novel BL/BLIs, ceftazidime/avibactam displayed better in vitro activity and thus is a rational treatment option for serine carbapenemase-harbouring P. aeruginosa. While imipenem/relebactam displayed some activity, particularly against isolates with blaKPC, meropenem/vaborbactam exhibited poor activity, with MICs similar to meropenem alone.
Topics: Meropenem; Ceftazidime; Carbapenems; beta-Lactamase Inhibitors; Pseudomonas aeruginosa; Lactams; Azabicyclo Compounds; Anti-Bacterial Agents; beta-Lactamases; Imipenem; Drug Combinations; Microbial Sensitivity Tests
PubMed: 37840005
DOI: 10.1093/jac/dkad225 -
Journal of Medical Microbiology Dec 2021Carbapenems are potent members of the β-lactam family that inhibit bacterial cell-wall biosynthesis inhibitors . They are highly effective against Gram-negative and... (Review)
Review
Carbapenems are potent members of the β-lactam family that inhibit bacterial cell-wall biosynthesis inhibitors . They are highly effective against Gram-negative and Gram-positive drug-resistant infections . As such, carbapenems are typically reserved as an antibiotic of last resort. The WHO lists meropenem as an essential medicine. Nausea and vomiting are reported in ≤20% of carbapenem recipients, with 1.5% suffering seizures. Enzymatic hydrolysis of the βlactam ring is the main driver of clinical resistance. These enzymes can be classified as Class A, B and D. Classes A and D are serine βlactamases, whereas Class B rely on metal-mediated hydrolysis, typically through zinc.
Topics: Anti-Bacterial Agents; Carbapenems; Meropenem; beta-Lactamases; beta-Lactams
PubMed: 34889726
DOI: 10.1099/jmm.0.001462 -
European Journal of Clinical... Sep 2023Carbapenemase-producing in Enterobacterales (CPE) represent a critical health concern worldwide, including in Switzerland, leading to very limited therapeutic options....
Carbapenemase-producing in Enterobacterales (CPE) represent a critical health concern worldwide, including in Switzerland, leading to very limited therapeutic options. Therefore, our aim was to evaluate the susceptibility to the novel ß-lactam/ß-lactamase inhibitor combinations ceftazidime-avibactam, meropenem-vaborbactam, and imipenem-relebactam of CPE isolates recovered in Switzerland from 2018 to 2020. A total of 150 clinical CPE were studied including mainly Klebsiella pneumoniae (n = 61, 40.3%) and Escherichia coli (n = 53, 35.3%). The distribution of carbapenemases was as follows: KPC-like (32%), OXA-48-like (32%), NDM-like (24%), combinations of carbapenemases (10%), VIM-1 producers (n = 2), and a single IMI-1 producer. Overall, 77% of the strains were susceptible to meropenem-vaborbactam, 63% was susceptible to ceftazidime-avibactam, and 62% susceptible to imipenem-relebactam. Those data may contribute to optimize the choice of first line therapy for treating infections due to CPE.
Topics: Humans; Meropenem; Switzerland; Anti-Bacterial Agents; Ceftazidime; beta-Lactamases; Bacterial Proteins; Drug Combinations; Imipenem; Microbial Sensitivity Tests; Klebsiella pneumoniae
PubMed: 37566365
DOI: 10.1007/s10096-023-04647-0