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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 -
Clinical Medicine & Research Sep 2021Both and have been regarded as important opportunistic pathogens for humans. Recent data have described the spread of multi-resistant strains of these organisms....
Both and have been regarded as important opportunistic pathogens for humans. Recent data have described the spread of multi-resistant strains of these organisms. Development of novel resistance phenotypes may result in a reduction in anti-infective efficacy, therefore making patient treatment decisions challenging. The Surveillance of Wisconsin Organisms for Trends in Antimicrobial Resistance and Epidemiology (SWOTARE) program aims to combat this issue and improve antibiotic stewardship by monitoring antimicrobial resistance at a local level. Multi-center laboratory surveillance, with testing at a single location utilizing standardized media and susceptibility testing protocols In the years 2018 and 2019, a total of 591 clinically-significant and 668 clinically-significant isolates were collected through this initiative; limited demographic data were also supplied. Isolates were tested by broth microdilution procedures advocated by Clinical and Laboratory Standards Institute. On a statewide level, both and demonstrated in vitro potency to carbapenem and aminoglycoside agents at rates exceeding 96%. isolates were generally more susceptible to cephem and monobactam agents than isolates; the converse was true for fluoroquinolone agents. Patterns of local antimicrobial resistance were revealed that were not apparent at the state level. isolates submitted from the Northcentral and Southeast regions demonstrated decreased susceptibility to five antimicrobial agents (notably third- and fourth-generation cephems) when compared to the state average. Isolates derived from males, older individuals, and urogenital sources exhibited decreased susceptibility to third- and fourth-generation cephem agents ( ≤ 0.047). With respect to , antimicrobial resistance phenotype was not a function of geography or gender. However, isolates emanating from older patients and the respiratory tract showed decreased susceptibility to ampicillin/sulbactam and cefazolin, respectively ( ≤ 0.019). Antimicrobial resistance surveillance at a local level provides utility to community/rural hospital clinicians, pharmacists, and infection control practitioners. With respect to , further surveillance efforts may be necessary in the Northcentral and Southeast regions of Wisconsin. Subanalysis of demographic data indicated cephem-resistance correlates that are not apparent at the statewide level.
Topics: Anti-Bacterial Agents; Drug Resistance, Bacterial; Enterobacter cloacae; Humans; Klebsiella pneumoniae; Male; Microbial Sensitivity Tests; Wisconsin
PubMed: 34531269
DOI: 10.3121/cmr.2021.1588 -
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 -
Microbiology Spectrum Oct 2022Carbapenem-resistant Pseudomonas aeruginosa (CRPA) is a pathogen of global concern due to the fact that therapeutic drugs are limited. Metallo-β-lactamase...
Carbapenem-resistant Pseudomonas aeruginosa (CRPA) is a pathogen of global concern due to the fact that therapeutic drugs are limited. Metallo-β-lactamase (MBL)-producing P. aeruginosa has become a critical part of CRPA. Alcaligenes faecalis metallo-β-lactamase (AFM) is a newly identified subclass B1b MBL. In this study, 487 P. aeruginosa strains isolated from patients and the environment in an intensive care unit were screened for AFM alleles. Five AFM-producing strains were identified, including four AFM-2-producing strains (ST262) and one AFM-4-producing strain (ST671). AFM-2-producing strains were isolated from rectal and throat swabs, and AFM-4-producing strains were isolated from the water sink. The carrying plasmids belonged to the IncP-2 type, while the carrying plasmid pAR19438 was a pSTY-like megaplasmid. Plasmid pAR19438 was acquired by the integration of the Tn-like transposon. All genes were embedded in an IS- unit core module flanked by class 1 integrons. The core module of was IS-Δ---Δ-ΔIS, while the core module of was IS-Δ---Δ-IS-----ΔIS. The flanking sequences of IS- units also differed. The expression of AFM-2 and AFM-4 in DH5α and PAO1 illustrated the same effect for the evaluation of the MICs of β-lactams, except for aztreonam. Identification of AFM-4 underscores that the quick spread and emerging development of mutants of MBLs require continuous surveillance in P. aeruginosa. Acquiring metallo-β-lactamase genes is one of the important carbapenem resistance mechanisms of P. aeruginosa. Alcaligenes faecalis metallo-β-lactamase is a newly identified metallo-β-lactamase, the prevalence and genetic context of which need to be explored. In this study, we identified AFM-producing P. aeruginosa strains among clinical isolates and found a new mutant of AFM, AFM-4. The carrying plasmid pAR19438 was a pSTY-like megaplasmid, unlike the plasmids encoding other alleles. The genetic context of was also different. However, AFM-2 and AFM-4 had the same impacts on antibiotic susceptibility. The presence and transmission of AFM alleles in P. aeruginosa pose a challenge to clinical practice.
Topics: Humans; Alleles; Anti-Bacterial Agents; Aztreonam; beta-Lactam Resistance; beta-Lactamases; Carbapenems; Microbial Sensitivity Tests; Plasmids; Pseudomonas aeruginosa; Pseudomonas Infections
PubMed: 36000902
DOI: 10.1128/spectrum.02035-22 -
Microbiology Spectrum Oct 2022The evolution of bacterial antibiotic resistance is exhausting the list of currently used antibiotics and endangers those in the pipeline. The combination of antibiotics...
The evolution of bacterial antibiotic resistance is exhausting the list of currently used antibiotics and endangers those in the pipeline. The combination of antibiotics is a promising strategy that may suppress resistance development and/or achieve synergistic therapeutic effects. Eravacycline is a newly approved antibiotic that is effective against a variety of multidrug-resistant (MDR) pathogens. However, the evolution of resistance to eravacycline and strategies to suppress the evolution remain unexplored. Here, we demonstrated that a carbapenem-resistant Klebsiella pneumoniae clinical isolate quickly developed resistance to eravacycline, which is mainly caused by mutations in the gene encoding the Lon protease. The evolved resistant mutants display collateral sensitivities to β-lactam/β-lactamase inhibitor (BLBLI) combinations aztreonam/avibactam and ceftazidime-avibactam. Proteomic analysis revealed upregulation of the multidrug efflux system AcrA-AcrB-TolC and porin proteins OmpA and OmpU, which contributed to the increased resistance to eravacycline and susceptibility to BLBLIs, respectively. The combination of eravacycline with aztreonam/avibactam or ceftazidime-avibactam suppresses resistance development. We further demonstrated that eravacycline-resistant mutants evolved from an NDM-1-containing K. pneumoniae strain display collateral sensitivity to aztreonam/avibactam, and the combination of eravacycline with aztreonam/avibactam suppresses resistance development. In addition, the combination of eravacycline with aztreonam/avibactam or ceftazidime-avibactam displayed synergistic therapeutic effects in a murine cutaneous abscess model. Overall, our results revealed mechanisms of resistance to eravacycline and collateral sensitivities to BLBLIs and provided promising antibiotic combinations in the treatment of multidrug-resistant K. pneumoniae infections. The increasing bacterial antibiotic resistance is a serious threat to global public health, which demands novel antimicrobial medicines and treatment strategies. Eravacycline is a newly approved antibiotic that belongs to the tetracycline antibiotics. Here, we found that a multidrug-resistant Klebsiella pneumoniae clinical isolate rapidly developed resistance to eravacycline and the evolved resistant mutants displayed collateral sensitivity to antibiotics aztreonam/avibactam and ceftazidime-avibactam. We demonstrated that the combination of eravacycline with aztreonam/avibactam or ceftazidime-avibactam repressed resistance development and improved the treatment efficacies. We also elucidated the mechanisms that contribute to the increased resistance to eravacycline and susceptibility to aztreonam/avibactam and ceftazidime-avibactam. This work demonstrated the mechanisms of antibiotic resistance and collateral sensitivity and provided a new therapeutically option for effective antibiotic combinations.
Topics: Mice; Animals; Klebsiella pneumoniae; Aztreonam; Drug Collateral Sensitivity; beta-Lactamase Inhibitors; Protease La; Proteomics; Microbial Sensitivity Tests; Azabicyclo Compounds; Anti-Bacterial Agents; Tetracyclines; Carbapenems; Porins; beta-Lactamases; Klebsiella Infections
PubMed: 35972286
DOI: 10.1128/spectrum.01390-22 -
Frontiers in Microbiology 2022β-lactam antibiotics are one of the most widely used and diverse classes of antimicrobial agents for treating both Gram-negative and Gram-positive bacterial infections.... (Review)
Review
β-lactam antibiotics are one of the most widely used and diverse classes of antimicrobial agents for treating both Gram-negative and Gram-positive bacterial infections. The β-lactam antibiotics, which include penicillins, cephalosporins, monobactams and carbapenems, exert their antibacterial activity by inhibiting the bacterial cell wall synthesis and have a global positive impact in treating serious bacterial infections. Today, β-lactam antibiotics are the most frequently prescribed antimicrobial across the globe. However, due to the widespread use and misapplication of β-lactam antibiotics in fields such as human medicine and animal agriculture, resistance to this superlative drug class has emerged in the majority of clinically important bacterial pathogens. This heightened antibiotic resistance prompted researchers to explore novel strategies to restore the activity of β-lactam antibiotics, which led to the discovery of β-lactamase inhibitors (BLIs) and other β-lactam potentiators. Although there are several successful β-lactam-β-lactamase inhibitor combinations in use, the emergence of novel resistance mechanisms and variants of β-lactamases have put the quest of new β-lactam potentiators beyond precedence. This review summarizes the success stories of β-lactamase inhibitors in use, prospective β-lactam potentiators in various phases of clinical trials and the different strategies used to identify novel β-lactam potentiators. Furthermore, this review discusses the various challenges in taking these β-lactam potentiators from bench to bedside and expounds other mechanisms that could be investigated to reduce the global antimicrobial resistance (AMR) burden.
PubMed: 36970185
DOI: 10.3389/fmicb.2022.1092556