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Frontiers in Cellular and Infection... 2023To evaluate the efficacy of ceftazidime-avibactam (CZA) and aztreonam-avibactam (AZA) against bloodstream infections (BSIs) or lower respiratory tract infections (LRTIs)...
Optimal treatment of ceftazidime-avibactam and aztreonam-avibactam against bloodstream infections or lower respiratory tract infections caused by extensively drug-resistant or pan drug-resistant (XDR/PDR) .
OBJECTIVE
To evaluate the efficacy of ceftazidime-avibactam (CZA) and aztreonam-avibactam (AZA) against bloodstream infections (BSIs) or lower respiratory tract infections (LRTIs) - caused by extensive drug-resistant or pan drug-resistant (XDR/PDR)
METHOD
The two-fold dilution method was used to determine the minimum inhibitory concentrations (MICs) of CZA/AZA against XDR/PDR . Whole-genome sequencing was used to analyze the resistance determinants of each isolate. Monte Carlo simulations (MCSs) were used to evaluate the probability of target attainment (PTA) and the cumulative fraction of response (CFR) of each CZA/AZA dosing regimen traditional infusion (TI)/optimized two-step-administration therapy (OTAT).
RESULTS
We found that XDR/PDR P. aeruginosa may carry some rare MBLs (e.g.: IND-6, SLB-1, THIN-B). isolates producing IMP-45, VIM-1, or VIM-2 were inhibited by AZA at a concentration of 2 to 8 mg/L. All isolates producing IND-6 plus other serine β-lactamases were high-level resistant to CZA/AZA (MICs >64 mg/L). All simulated dosing regimens of CZA/AZA against BSIs-causing XDR/PDR achieved 100% PTA when the MIC was ≤32 mg/L.
CONCLUSION
AZA has been considered as an option for the treatment of infections caused by XDR/PDR producing IMP-45, VIM-1, or VIM-2. OTAT with sufficient pharmacodynamic exposure may be an optimal treatment option for XDR/PDR with a high-level MIC of CZA/AZA.
Topics: Humans; Aztreonam; Anti-Bacterial Agents; Pseudomonas aeruginosa; Pharmaceutical Preparations; Drug Combinations; Respiratory Tract Infections; Sepsis; beta-Lactamases; Microbial Sensitivity Tests; Pseudomonas Infections
PubMed: 37457958
DOI: 10.3389/fcimb.2023.1023948 -
The Journal of Antimicrobial... Nov 2021Multi-drug resistant (MDR) Gram-negative bacteria represent a growing threat, with an increasing prevalence of carbapenem-resistant Enterobacterales (CRE) infections,... (Review)
Review
Multi-drug resistant (MDR) Gram-negative bacteria represent a growing threat, with an increasing prevalence of carbapenem-resistant Enterobacterales (CRE) infections, for which treatment options are limited. New treatment combinations composed of a β-lactam antibiotic plus a potent β-lactamase inhibitor (BLI) with anti-carbapenemase activity have been developed, including two carbapenem/BLI combinations that are commercially available-meropenem/vaborbactam (Vabomere® in the US, Vaborem® in Europe; Melinta Therapeutics) and imipenem/cilastatin/relebactam (Recarbrio®; Merck Sharp & Dohme), plus one other (meropenem/nacubactam) in early clinical development. This review provides a summary of the preclinical evidence supporting the use of carbapenem/BLI combinations and presents the clinical evidence across a range of MDR Gram-negative infections, with a focus on the use of meropenem/vaborbactam. All three BLIs have shown in vivo activity against Klebsiella pneumoniae carbapenemase and other class A carbapenemases. In 2019, meropenem/vaborbactam was listed in the WHO's list of essential medicines, because of its activity against priority 1 antibiotic-resistant pathogens. Meropenem/vaborbactam has considerable in vitro and in vivo activity against CRE, and in vitro evidence showing a low potential for resistance at clinically relevant doses. In randomized trials, meropenem/vaborbactam was non-inferior to piperacillin/tazobactam in patients with complicated urinary tract infection and more effective than the best-available treatment in patients with serious CRE infections. Meropenem/vaborbactam is well tolerated and, based on clinical experience, demonstrated lower toxicity compared with the combination regimens that have previously been the standard of care. In conclusion, carbapenem/BLI combinations represent an important therapeutic strategy in patients with MDR Gram-negative infections.
Topics: Anti-Bacterial Agents; Carbapenems; Drug Resistance, Multiple, Bacterial; Humans; Monobactams; beta-Lactamase Inhibitors
PubMed: 34849998
DOI: 10.1093/jac/dkab353 -
BioMed Research International 2023Antimicrobial resistance (AMR) is a significant public health issue in Bangladesh like many other developing countries where data on resistance trends are scarce.... (Review)
Review
Antimicrobial resistance (AMR) is a significant public health issue in Bangladesh like many other developing countries where data on resistance trends are scarce. Moreover, the existence of multidrug-resistant (MDR) exerts an ominous effect on the poultry sector. Therefore, the current systematic review, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, was conducted to find out the AMR scenarios in isolates sourced from poultry and poultry environments in Bangladesh between 2010 and 2021. Following the PRISMA guidelines, a total of 17 published scientific articles were selected for this systematic review. This review revealed that 18 out of 64 districts in Bangladesh reported in poultry, having a higher prevalence (combined prevalence: 69.3%, 95% confidence interval, CI: 67.3-71%). Moreover, the prevalence ranged from 24.3% to 100%. This review found that isolates showed resistance to 14 antimicrobial classes and 45 different antimicrobial agents, including the last-line (reserve group) antibiotics and banned antimicrobial categories for the treatment of infections in agricultural animals. Phenotypic resistance of against penicillins and beta-lactamase inhibitors (20.2%-100%), cephalosporins (1.9%-100%), fluoroquinolones (5.98%-100%), aminoglycosides (6%-100%), tetracyclines (17.7%-100%), carbapenems (13.6%-72.7%), macrolides (11.8%-100%), polymyxins (7.9%-100%), phenicols (20%-97.2%), sulfa drugs (44.7%-100%), cephamycins (21.4%-48.8%), nitrofurans (21.4%-63.2%), monobactams (1.2%), and glycylcyclines (2.3%) was recorded in the last decades in Bangladesh. Also, 14 articles reported MDR in poultry, including a 100% MDR in nine articles and a 92.7% (95% CI: 91.2-94%) combined percentage of MDR isolates. Twenty-four different AMR genes encoding resistance to beta-lactams ( , , , , , , , and ), colistin ( and ), fluoroquinolones ( and ), tetracyclines (, , and ), sulfonamides ( and ), trimethoprim (), aminoglycosides (), streptomycin (), gentamicin (), erythromycin (), and chloramphenicol ( and ) were detected in isolates. The presence of MDR and their corresponding resistance genes in poultry and poultry environments is an alarming issue for all health communities in Bangladesh. We suggest a regular antimicrobial surveillance program with a strong One Health approach to lessen the hazardous effects of AMR in poultry industries in Bangladesh.
Topics: Animals; Escherichia coli; Poultry; Bangladesh; Anti-Bacterial Agents; Anti-Infective Agents; Escherichia coli Infections; Aminoglycosides; Fluoroquinolones; Tetracyclines; Microbial Sensitivity Tests
PubMed: 36778056
DOI: 10.1155/2023/2425564 -
Microbiology Spectrum Jun 2024This study aimed to assess the efficacy of ceftazidime-avibactam (CZA) in combination with various antimicrobial agents against carbapenem-resistant (CRKP). We...
UNLABELLED
This study aimed to assess the efficacy of ceftazidime-avibactam (CZA) in combination with various antimicrobial agents against carbapenem-resistant (CRKP). We selected 59 clinical CRKP isolates containing distinct drug resistance mechanisms. The minimum inhibitory concentrations (MICs) of meropenem (MEM), colistin (COL), eravacycline (ERA), amikacin (AK), fosfomycin (FOS), and aztreonam (ATM), both individually and in combination with CZA, were tested using the checkerboard method. The interactions of antimicrobial agent combinations were assessed by fractional inhibitory concentration index (FICI) and susceptible breakpoint index (SBPI). The time-kill curve assay was employed to dynamically evaluate the effects of these drugs alone and in combination format. In the checkerboard assay, the combination of CZA+MEM showed the highest level of synergistic effect against both KPC-producing and carbapenemase-non-producing isolates, with synergy rates of 91.3% and 100%, respectively. Following closely was the combination of FOS+CZA . For metallo-beta-lactamases (MBLs) producing strains, ATM+CZA displayed complete synergy, while the combination of MEM+CZA showed a synergy rate of only 57.14% for NDM-producing strains and 91.67% for IMP-producing strains. In the time-kill assay, MEM+CZA also demonstrated significant synergistic effects against the two KPC-2-producing isolates (Y070 and L70), the two carbapenemase-non-producing isolates (Y083 and L093), and the NDM-1-producing strain L13, with reductions in log CFU/mL exceeding 10 compared to the control. Against the IMP-producing strain Y047, ATM+CZA exhibited the highest synergistic effect, resulting in a log CFU/mL reduction of 10.43 compared to the control. The combination of CZA and MEM exhibited good synergistic effects against KPC-producing and non-enzyme-producing strains, followed by the FOS+CZA combination. Among MBL-producing strains, ATM+CZA demonstrated the most pronounced synergistic effect. However, the combinations of CZA with ERA, AK, and COL show irrelevant effects against the tested clinical isolates.
IMPORTANCE
Our study confirmed the efficacy of the combination CZA+MEM against KPC-producing and non-carbapenemase-producing strains. For metalloenzyme-producing strains, CZA+ATM demonstrated the most significant synergy. Additionally, CZA exhibited a notable synergy effect when combined with FOS. These combination therapies present promising new options for the treatment of CRKP infection.
Topics: Azabicyclo Compounds; Klebsiella pneumoniae; Ceftazidime; Drug Combinations; Microbial Sensitivity Tests; Humans; Anti-Bacterial Agents; Klebsiella Infections; Carbapenem-Resistant Enterobacteriaceae; Drug Synergism; beta-Lactamases; Carbapenems; Drug Resistance, Multiple, Bacterial; Bacterial Proteins; Fosfomycin; Aztreonam
PubMed: 38712934
DOI: 10.1128/spectrum.00107-24 -
Cureus Jul 2023Introduction Resistance due to AmpC and extended-spectrum beta (β)-lactamases (ESBLs) in is an emerging problem worldwide. AmpC enzymes are a subclass of β-lactamases...
Introduction Resistance due to AmpC and extended-spectrum beta (β)-lactamases (ESBLs) in is an emerging problem worldwide. AmpC enzymes are a subclass of β-lactamases that have a capacity to hydrolyze and deactivate a large range of β-lactam antibiotics, particularly cephalosporins, penicillins, and monobactams, although frequently being susceptible to carbapenems and fourth-generation cephalosporins. The prevalence of plasmid-mediated AmpC (pAmpC) genotypes in uropathogenic isolates were looked at a tertiary care teaching hospital of Western Uttar Pradesh. Materials and methods A total of 312 non-repeat clinical isolates among patients presented with urinary tract infections (UTIs) were investigated by standard microbiological methods. Isolates were screened for the presence of ampC using a cefoxitin (30 µg) disc and confirmed using an inhibitor-based assay. Using multiplex polymerase chain reaction (PCR), six AmpC genotypes, namely, CIT, DHA, EBC, ACC, FOX, and MOX, were genotypically identified. Results A total of 152 (48.72%) uropathogenic isolates tested positive on the cefoxitin screening. Out of which, AmpC production was confirmed in 118/152 (77.63%) using a phenotypic method. In particular, the pAmpC gene was found in 56/152 (36.84%) isolates. CIT was the most common gene detected in this geographical area (57.14 %). Multiple genes, i.e., CIT and FOX, were also detected in 14.29% of the isolates. Conclusion Identifying AmpC producers is important in routine microbiology laboratory as they are a nosocomial threat requiring strict adherence to infection control protocols. A confirmatory phenotypic test followed by genotypic tests will help in the correct and accurate identification of this resistance.
PubMed: 37565104
DOI: 10.7759/cureus.41551 -
Clinical Infectious Diseases : An... May 2023Sulbactam-durlobactam is a β-lactam/β-lactamase inhibitor combination currently in development for the treatment of infections caused by Acinetobacter, including... (Review)
Review
The Pharmacokinetics/Pharmacodynamic Relationship of Durlobactam in Combination With Sulbactam in In Vitro and In Vivo Infection Model Systems Versus Acinetobacter baumannii-calcoaceticus Complex.
Sulbactam-durlobactam is a β-lactam/β-lactamase inhibitor combination currently in development for the treatment of infections caused by Acinetobacter, including multidrug-resistant (MDR) isolates. Although sulbactam is a β-lactamase inhibitor of a subset of Ambler class A enzymes, it also demonstrates intrinsic antibacterial activity against a limited number of bacterial species, including Acinetobacter, and has been used effectively in the treatment of susceptible Acinetobacter-associated infections. Increasing prevalence of β-lactamase-mediated resistance, however, has eroded the effectiveness of sulbactam in the treatment of this pathogen. Durlobactam is a rationally designed β-lactamase inhibitor within the diazabicyclooctane (DBO) class. The compound demonstrates a broad spectrum of inhibition of serine β-lactamase activity with particularly potent activity against class D enzymes, an attribute which differentiates it from other DBO inhibitors. When combined with sulbactam, durlobactam effectively restores the susceptibility of resistant isolates through β-lactamase inhibition. The present review describes the pharmacokinetic/pharmacodynamic (PK/PD) relationship associated with the activity of sulbactam and durlobactam established in nonclinical infection models with MDR Acinetobacter baumannii isolates. This information aids in the determination of PK/PD targets for efficacy, which can be used to forecast efficacious dose regimens of the combination in humans.
Topics: Humans; Sulbactam; beta-Lactamase Inhibitors; Acinetobacter baumannii; Anti-Bacterial Agents; Acinetobacter Infections; Monobactams; beta-Lactamases; Microbial Sensitivity Tests
PubMed: 37125469
DOI: 10.1093/cid/ciad096 -
The Journal of Pediatric Pharmacology... 2022Intravenous beta-lactam antibiotics are the most prescribed antibiotic class in US hospitalized patients of all ages; therefore, optimizing their dosing is crucial....
Intravenous beta-lactam antibiotics are the most prescribed antibiotic class in US hospitalized patients of all ages; therefore, optimizing their dosing is crucial. Bactericidal killing is best predicted by the time in which beta-lactam drug concentrations are maintained above the organism's minimum inhibitory concentration (MIC), rather than achievement of a high peak concentration. As such, administration of beta-lactam antibiotics via extended or continuous infusions over a minimum of 3 hours, rather than standard infusions over approximately 30 minutes, has been associated with improved achievement of pharmacodynamic targets and improved clinical outcomes in adult medical literature. This review summarizes the pediatric medical literature. Applicable studies include pharmacodynamic models, case series, retrospective analyses, and prospective studies on the use of extended infusion and continuous infusion penicillins, cephalosporins, carbapenems, and monobactams in neonates, infants, children, and adolescents. Specialized patient populations with unique pharmacokinetics and high-risk infections (neonates, critically ill, febrile neutropenia, cystic fibrosis) are also reviewed. While more studies are needed to confirm prospective clinical outcomes, the current body of evidence suggests extended and continuous infusions of beta-lactam antibiotics are well tolerated in children and improve achievement of pharmacokineticpharmacodynamic targets with similar or superior clinical outcomes, particularly in infections associated with high MICs.
PubMed: 35350159
DOI: 10.5863/1551-6776-27.3.214 -
MBio Feb 2023The purine-derived signaling molecules c-di-AMP and (p)ppGpp control /PBP2a-mediated β-lactam resistance in methicillin-resistant Staphylococcus aureus (MRSA) raise the...
The purine-derived signaling molecules c-di-AMP and (p)ppGpp control /PBP2a-mediated β-lactam resistance in methicillin-resistant Staphylococcus aureus (MRSA) raise the possibility that purine availability can control antibiotic susceptibility. Consistent with this, exogenous guanosine and xanthosine, which are fluxed through the GTP branch of purine biosynthesis, were shown to significantly reduce MRSA β-lactam resistance. In contrast, adenosine (fluxed to ATP) significantly increased oxacillin resistance, whereas inosine (which can be fluxed to ATP and GTP via hypoxanthine) only marginally increased oxacillin susceptibility. Furthermore, mutations that interfere with purine synthesis ( operon), transport (NupG, PbuG, PbuX) and the salvage pathway (DeoD2, Hpt) increased β-lactam resistance in MRSA strain JE2. Increased resistance of a mutant was not significantly reversed by guanosine, indicating that NupG is required for guanosine transport, which is required to reduce β-lactam resistance. Suppressor mutants resistant to oxacillin/guanosine combinations contained several purine salvage pathway mutations, including and . Guanosine significantly increased cell size and reduced levels of c-di-AMP, while inactivation of GdpP, the c-di-AMP phosphodiesterase negated the impact of guanosine on β-lactam susceptibility. PBP2a expression was unaffected in or mutants, suggesting that guanosine-induced β-lactam susceptibility may result from dysfunctional c-di-AMP-dependent osmoregulation. These data reveal the therapeutic potential of purine nucleosides, as β-lactam adjuvants that interfere with the normal activation of c-di-AMP are required for high-level β-lactam resistance in MRSA. The clinical burden of infections caused by antimicrobial resistant (AMR) pathogens is a leading threat to public health. Maintaining the effectiveness of existing antimicrobial drugs or finding ways to reintroduce drugs to which resistance is widespread is an important part of efforts to address the AMR crisis. Predominantly, the safest and most effective class of antibiotics are the β-lactams, which are no longer effective against methicillin-resistant Staphylococcus aureus (MRSA). Here, we report that the purine nucleosides guanosine and xanthosine have potent activity as adjuvants that can resensitize MRSA to oxacillin and other β-lactam antibiotics. Mechanistically, exposure of MRSA to these nucleosides significantly reduced the levels of the cyclic dinucleotide c-di-AMP, which is required for β-lactam resistance. Drugs derived from nucleotides are widely used in the treatment of cancer and viral infections highlighting the clinical potential of using purine nucleosides to restore or enhance the therapeutic effectiveness of β-lactams against MRSA and potentially other AMR pathogens.
Topics: Methicillin-Resistant Staphylococcus aureus; Purine Nucleosides; Bacterial Proteins; Anti-Bacterial Agents; Oxacillin; beta-Lactams; Monobactams; Guanosine; Adenosine Triphosphate; Guanosine Triphosphate; Microbial Sensitivity Tests; Penicillin-Binding Proteins; beta-Lactam Resistance
PubMed: 36507833
DOI: 10.1128/mbio.02478-22 -
Antimicrobial Resistance and Infection... Aug 2020The emergence and spread of antimicrobial resistance (AMR) present a challenge to disease control in East Africa. Resistance to beta-lactams, which are by far the most... (Review)
Review
BACKGROUND
The emergence and spread of antimicrobial resistance (AMR) present a challenge to disease control in East Africa. Resistance to beta-lactams, which are by far the most used antibiotics worldwide and include the penicillins, cephalosporins, monobactams and carbapenems, is reducing options for effective control of both Gram-positive and Gram-negative bacteria. The World Health Organization, Food and Agricultural Organization and the World Organization for Animal Health have all advocated surveillance of AMR using an integrated One Health approach. Regional consortia also have strengthened collaboration to address the AMR problem through surveillance, training and research in a holistic and multisectoral approach. This review paper contains collective information on risk factors for transmission, clinical relevance and diversity of resistance genes relating to extended-spectrum beta-lactamase-producing (ESBL) and carbapenemase-producing Enterobacteriaceae, and Methicillin-resistant Staphylococcus aureus (MRSA) across the human, animal and environmental compartments in East Africa.
MAIN BODY
The review of the AMR literature (years 2001 to 2019) was performed using search engines such as PubMed, Scopus, Science Direct, Google and Web of Science. The search terms included 'antimicrobial resistance and human-animal-environment', 'antimicrobial resistance, risk factors, genetic diversity, and human-animal-environment' combined with respective countries of East Africa. In general, the risk factors identified were associated with the transmission of AMR. The marked genetic diversity due to multiple sequence types among drug-resistant bacteria and their replicon plasmid types sourced from the animal, human and environment were reported. The main ESBL, MRSA and carbapenem related genes/plasmids were the CTX-Ms (45.7%), SCCmec type III (27.3%) and IMP types (23.8%), respectively.
CONCLUSION
The high diversity of the AMR genes suggests there may be multiple sources of resistance bacteria, or the possible exchange of strains or a flow of genes amongst different strains due to transfer by mobile genetic elements. Therefore, there should be harmonized One Health guidelines for the use of antibiotics, as well as regulations governing their importation and sale. Moreover, the trend of ESBLs, MRSA and carbapenem resistant (CAR) carriage rates is dynamic and are on rise over time period, posing a public health concern in East Africa. Collaborative surveillance of AMR in partnership with regional and external institutions using an integrated One Health approach is required for expert knowledge and technology transfer to facilitate information sharing for informed decision-making.
Topics: Africa, Eastern; Animals; Anti-Bacterial Agents; Bacterial Infections; Bacterial Proteins; Carbapenems; Drug Resistance, Bacterial; Environmental Microbiology; Genetic Variation; Gram-Negative Bacteria; Gram-Positive Bacteria; Humans; Risk Factors; beta-Lactamases
PubMed: 32762743
DOI: 10.1186/s13756-020-00786-7 -
Nature Communications Jul 2023Penicillin-binding proteins (PBPs) are essential for the formation of the bacterial cell wall. They are also the targets of β-lactam antibiotics. In Enterococcus...
Penicillin-binding proteins (PBPs) are essential for the formation of the bacterial cell wall. They are also the targets of β-lactam antibiotics. In Enterococcus faecium, high levels of resistance to β-lactams are associated with the expression of PBP5, with higher levels of resistance associated with distinct PBP5 variants. To define the molecular mechanism of PBP5-mediated resistance we leveraged biomolecular NMR spectroscopy of PBP5 - due to its size (>70 kDa) a challenging NMR target. Our data show that resistant PBP5 variants show significantly increased dynamics either alone or upon formation of the acyl-enzyme inhibitor complex. Furthermore, these variants also exhibit increased acyl-enzyme hydrolysis. Thus, reducing sidechain bulkiness and expanding surface loops results in increased dynamics that facilitates acyl-enzyme hydrolysis and, via increased β-lactam antibiotic turnover, facilitates β-lactam resistance. Together, these data provide the molecular basis of resistance of clinical E. faecium PBP5 variants, results that are likely applicable to the PBP family.
Topics: Penicillin-Binding Proteins; Anti-Bacterial Agents; Bacterial Proteins; beta-Lactam Resistance; Monobactams; beta-Lactams; Microbial Sensitivity Tests; Hexosyltransferases
PubMed: 37460557
DOI: 10.1038/s41467-023-39966-5