scholarly journals Potent, specific MEPicides for treatment of zoonotic staphylococci

2019 ◽  
Author(s):  
Rachel L. Edwards ◽  
Isabel Heueck ◽  
Soon Goo Lee ◽  
Ishaan T. Shah ◽  
Andrew J. Jezewski ◽  
...  
Keyword(s):  
Antimicrobial Agents ◽  
Opportunistic Infections ◽  
Multidrug Resistant ◽  
Isoprenoid Biosynthesis ◽  
Forward Genetics ◽  
Microbial Pathogens ◽  
Cellular Transport ◽  
Human Welfare ◽  
Zoonotic Infections ◽  
Tract Infections

AbstractCoagulase-positive staphylococci, which frequently colonize the mucosal surfaces of animals, also cause a spectrum of opportunistic infections including skin and soft tissue infections, urinary tract infections, pneumonia, and bacteremia. However, recent advances in bacterial identification have revealed that these common veterinary pathogens are in fact, zoonoses that cause serious infections in human patients. The global spread of multidrug-resistant zoonotic staphylococci, in particular the emergence of methicillin-resistant organisms, is now a serious threat to both animal and human welfare. Accordingly, new therapeutic targets that can be exploited to combat staphylococcal infections are urgently needed. Enzymes of the methylerythritol phosphate pathway (MEP) of isoprenoid biosynthesis represent potential targets for treating zoonotic staphylococci. Here we demonstrate that fosmidomycin (FSM) inhibits the first step of the isoprenoid biosynthetic pathway catalyzed by deoxyxylulose phosphate reductoisomerase (DXR) in staphylococci. In addition, we have both enzymatically and structurally determined the mechanism by which FSM elicits its effect. Using a forward genetic screen, the glycerol-3-phosphate transporter GlpT that facilitates FSM uptake was identified in two zoonotic staphylococci, Staphylococcus schleiferi and Staphylococcus pseudintermedius. A series of lipophilic ester prodrugs (termed MEPicides) structurally related to FSM were synthesized, and data indicate that the presence of the prodrug moiety not only substantially increased potency of the inhibitors against staphylococci, but also bypassed the need for GlpT-mediated cellular transport. Collectively, our data indicate that the prodrug MEPicides selectively and robustly inhibit DXR in zoonotic staphylococci, and further, DXR represents a promising, druggable target for future development.Author SummaryThe proliferation of microbial pathogens resistant to the current pool of antibiotics is a major threat to public health. Drug resistance is pervasive in staphylococci, including several species that can cause serious zoonotic infections in humans. Thus, new antimicrobial agents are urgently need to combat these life-threatening, resistant infections. Here we establish the MEP pathway as a promising new target against zoonotic staphylococci. We determine that fosmidomycin (FSM) selectively targets the isoprenoid biosynthesis pathway in zoonotic staphylococci, and use forward genetics to identify the transporter that facilitates phosphonate antibiotic uptake. Employing this knowledge, we synthesized a series of potent antibacterial prodrugs that circumvent the transporter. Together, these novel prodrug inhibitors represent promising leads for further drug development against zoonotic staphylococci.

scholarly journals Intravenous Fosfomycin: An Assessment of Its Potential for Use in the Treatment of Systemic Infections in Canada

2018 ◽  
Vol 2018 ◽  
pp. 1-13 ◽  
Author(s):  
George G. Zhanel ◽  
Michael A. Zhanel ◽  
James A. Karlowsky
Keyword(s):  
Antimicrobial Agents ◽  
Multidrug Resistant ◽  
Hospitalized Patients ◽  
Second Line ◽  
Pharmacological Interactions ◽  
Term Administration ◽  
Excellent Safety Profile ◽  
Tract Infections ◽  
Systemic Infections

Fosfomycin is a bactericidal agent that inhibits cell wall synthesis using a mechanism of action distinct from β-lactams or other antimicrobial agents. It is a broad-spectrum agent that is frequently active against antimicrobial-resistant bacterial pathogens including methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE), multidrug-resistant (MDR) Enterobacteriaceae, and some isolates of MDR Pseudomonas aeruginosa. Intravenous fosfomycin has been prescribed for a wide variety of infections in many countries for >40 years. It is most frequently used in combination with other antimicrobial agents (e.g., β-lactams, carbapenems, and aminoglycosides) and has an excellent safety profile, including in neonates and children, even with long-term administration (weeks). Fosfomycin achieves extensive tissue distribution including difficult to reach compartments such as aqueous humor, vitreous humor, abscess fluid, and CSF. Available data, to date, suggest no clinically relevant pharmacological interactions between fosfomycin and other agents, including drugs, stimulants, or food. Intravenous fosfomycin’s role in therapy in Canada is likely as an agent used alone or in combination for complicated urinary tract infections in hospitalized patients as well as hospitalized patients with MDR infections who have not responded to first-, and potentially, second-line antimicrobials or in patients who cannot tolerate (due to adverse effects) first- and second-line antimicrobials.

Isolation and Identification of Multidrug-Resistant Isolates of Uropathogenic Klebsiella spp in Dogs

2021 ◽  
Vol 3 (1) ◽  
pp. 6-12
Author(s):  
M Mustapha ◽  
P Goel
Keyword(s):  
Antimicrobial Agents ◽  
Bacterial Species ◽  
Multidrug Resistant ◽  
Urine Samples ◽  
Penicillin G ◽  
Isolation And Identification ◽  
Sensitivity Testing ◽  
Bacterial Organism ◽  
Tract Infections ◽  
Klebsiella Spp

The most widespread ailments in dogs are urinary tract infections (UTIs) caused by bacterial species. It is necessary to recognize the prevailing bacterial pathogens and their susceptibility to antimicrobial agents to effectively treat UTIs. The present study aimed to classify the bacterial organism that causes UTIs in dogs and their patterns of antimicrobial resistance. A total of 141 urine samples were collected from diseased dogs in Veterinary Clinical Complex LUVAS in Hisar, India. Culture, biochemical and sensitivity testing were performed for each of the urine samples based on standard method. Of the total 141 urine samples from dogs, 21 (14.9%) isolates were identified as Klebsiella spp. The isolates were found to be highly resistant to ampicillin (100%), penicillin G (100%), oxytetracycline (100%), enrofloxacin (85.7%), chloramphenicol (80.6%), ceftriaxone (76.2%) and cloxacillin (71.4%), while susceptibility was observed against gentamicin (100%), amikacin (100%) and neomycin (90.5%). In the current study, 19 out of 21 identified isolates were found to be multidrug-resistant. This study indicates that dogs in the study area are found to harbor highly resistant Klebsiella spp. Therefore, when deciding on the antibiotic regimen for UTIs cases, Vets should consider resistance profile of chosen antibacterial agents before usage in order to discourage dissemination of resistant organisms in the study area.

scholarly journals Characterization of auto-agglutinating and non-typeable uropathogenic Escherichia coli strains

2019 ◽  
Vol 13 (06) ◽  
pp. 465-472
Author(s):  
Ulises Hernández-Chiñas ◽  
Alejandro Pérez-Ramos ◽  
Laura Belmont-Monroy ◽  
María E Chávez-Berrocal ◽  
Edgar González-Villalobos ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Virulence Genes ◽  
Antimicrobial Agents ◽  
Multidrug Resistant ◽  
Uropathogenic Escherichia Coli ◽  
E Coli ◽  
Resistant Strains ◽  
Tract Infections ◽  
Disk Method

Introduction: Uropathogenic Escherichia coli (UPEC) are the main etiological agent of urinary tract infections (UTIs). Association between different serotypes and UTIs is known, however, some strains are incapable to be serotyped. The aim of this work was to study bthe phenotypical and genotypical characteristics of 113 non-typeable (NT) and auto-agglutinating (AA) E. coli strains, isolated from UTIs in children and adults. Methodology: The 113 UPEC strains were analyzed by PCR assays using specific primers to determine their serogroups, fimH, papC, iutA, sat, hlyCA and cnf1, virulence associated genes, and chuA, yjaA and TSPE4.C2 for phylogroup determination. Additionally, the diffusion disk method was performed to evaluate the antimicrobial resistance to 18 antimicrobial agents. Results: Using the PCR assay, 63% (71) of the strains were genotyped showing O25 and O75 as the most common serogroups. The virulence genes fimH (86%) and iutA (74%) were the most prevalent, in relation to the phylogroups the commensal (A and B1) and virulent (B2 and D) showed similar frequencies (P > 0.05). The antimicrobial susceptibility test showed a high percentage (73%) of multidrug-resistant strains. Conclusions: The genotyping allowed identifying the serogroup in many of the strains that could not be typed by traditional serology. The strains carried virulence genes and were multidrug-resistant in both, commensal and virulent phylogroups. Our findings revealed that, in addition to the classical UPEC serogroups, there are pathogenic serogroups not reported yet.

scholarly journals Antimicrobial Susceptibility and Characterization of Resistance Mechanisms of Corynebacterium urealyticum Clinical Isolates

Antibiotics ◽  
2020 ◽  
Vol 9 (7) ◽  
pp. 404
Author(s):  
Itziar Chapartegui-González ◽  
Marta Fernández-Martínez ◽  
Ana Rodríguez-Fernández ◽  
Danilo J. P. Rocha ◽  
Eric R. G. R. Aguiar ◽  
...  
Keyword(s):  
Antimicrobial Susceptibility ◽  
Antimicrobial Agents ◽  
Point Mutations ◽  
Tetracycline Resistance ◽  
Multidrug Resistant ◽  
Resistance Mechanisms ◽  
Resistance Rate ◽  
Clinical Isolates ◽  
Tract Infections ◽  
Corynebacterium Urealyticum

Corynebacterium urealyticum is a non-diphtherial urease-producing clinically relevant corynebacterial, most frequently involved in urinary tract infections. Most of the C. urealyticum clinical isolates are frequently resistant to several antibiotics. We investigated the susceptibility of 40 C. urealyticum isolated in our institution during the period 2005–2017 to eight compounds representative of the main clinically relevant classes of antimicrobial agents. Antimicrobial susceptibility was determined by the Epsilometer test. Resistance genes were searched by PCR. All strains were susceptible to vancomycin whereas linezolid and rifampicin also showed good activity (MICs90 = 1 and 0.4 mg/L, respectively). Almost all isolates (39/40, 97.5%) were multidrug resistant. The highest resistance rate was observed for ampicillin (100%), followed by erythromycin (95%) and levofloxacin (95%). Ampicillin resistance was associated with the presence of the blaA gene, encoding a class A β-lactamase. The two rifampicin-resistant strains showed point mutations driving amino acid replacements in conserved residues of RNA polymerase subunit β (RpoB). Tetracycline resistance was due to an efflux-mediated mechanism. Thirty-nine PFGE patterns were identified among the 40 C. urealyticum, indicating that they were not clonally related, but producing sporadic infections. These findings raise the need of maintaining surveillance strategies among this multidrug resistant pathogen.

scholarly journals 1534. Polymyxin Antimicrobial Susceptibility (AST) Testing and Breakpoints for P. aeruginosa, A. baumannii, and Enterobacteriaceae: Recommendations from the United States Committee on Antimicrobial Susceptibility Testing (USCAST)

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S559-S559
Author(s):  
Jason M Pogue ◽  
Ronald N Jones ◽  
John S Bradley ◽  
David Andes ◽  
Sujata M Bhavnani ◽  
...  
Keyword(s):  
Antimicrobial Susceptibility ◽  
Antimicrobial Agents ◽  
Package Insert ◽  
Polymyxin B ◽  
The United States ◽  
Multidrug Resistant ◽  
Outcome Data ◽  
Published Data ◽  
Tract Infections

Abstract Background Polymyxins are important antimicrobial agents for the treatment of infections due to carbapenem-resistant and other multidrug-resistant organisms. Recently, the CLSI and EUCAST have set breakpoints for colistin (EUCAST and CLSI) and polymyxin B (CLSI) with slight differences in recommendations. However, there are issues unique to the polymyxin class that warrant additional guidances. Herein, we assess data related to breakpoint setting and make additional recommendations for polymyxin AST interpretive criteria. Methods Data sources included longitudinal (2011–2017) US surveillance reference broth microdilution (BMD) MIC distributions (128,573 isolates) for colistin and polymyxin B (PB), published data on accuracy of various AST methodologies, in vivo pharmacokinetic/pharmacodynamic (PK-PD) models, prior polymyxin guidelines and agency package insert dosing recommendations, and population PK-PD and toxicodynamic (TD) data. Epidemiological cut-off, PK-PD (and TD), and clinical data were all considered for susceptible (S) breakpoint determinations. Results Data demonstrate that the most commonly utilized AST methodologies (disk diffusion, Etest, and automated MIC susceptibility panels), as well as agar dilution testing cannot reliably detect resistance; and BMD is the preferred AST. Importantly, colistin S is a reliable surrogate for PB S with cross-S accuracy at > 99% of isolates in each pathogen group. Breakpoint recommendations can be found in the Table with emphasis on applying combination therapy. Key recommendations include an S breakpoint of ≤2 mg/L for each pathogen (both colistin and PB). However, based on a lack of preclinical efficacy in murine pneumonia models, PK/PD concerns, and poor clinical outcome data, we strongly suggest that no breakpoints are applied for pneumonia and that alternative therapies should be used where available. Additionally, due to a lack of significant renal excretion, PB will also have no S breakpoint recommendation for lower urinary tract infections. Conclusion The polymyxins have compromising characteristics that make them suboptimal antimicrobials when used alone, and additional caveats are required for AST breakpoint interpretive criteria and stewardship programs. Disclosures All authors: No reported disclosures.

scholarly journals A Review of the Innate Immune Evasion Mechanisms and Status of Vaccine Development of Klebsiella pneumonia

2021 ◽  
pp. 33-47
Author(s):  
Fredrick Ruo Tiria ◽  
Lillian Musila
Keyword(s):  
Immune Evasion ◽  
Antimicrobial Agents ◽  
Vaccine Development ◽  
Bloodstream Infections ◽  
Multidrug Resistant ◽  
Immune Defense ◽  
Klebsiella Pneumonia ◽  
High Morbidity ◽  
Pharmaceutical Industries ◽  
Tract Infections

Klebsiella pneumoniae (KP) is a human pathogen causing a broad spectrum of diseases such as urinary tract infections (UTI), pneumonia, pyogenic liver abscess, bloodstream infections, and sepsis. Neonate, geriatric and immunocompromised individuals are the most vulnerable to KP infections. The success of KP as an infectious agent is due to the evolution of various mechanisms to evade the host's immune system. These diverse mechanisms have led to the dominance of KP infections in community settings where hypervirulent strains predominate and in hospital-acquired infections where multidrug-resistant strains predominate. KP infections in the past decades have been increasingly associated with high morbidity and mortality due to the emergence of multidrug-resistant and hypervirulent strains capable of evading both the internal immune defense mechanisms and external antimicrobial agents. The pharmaceutical industries have very few and often expensive new antibiotics in the pipeline, offering little hope for antibiotic therapy. The development of new therapeutic strategies such as polyvalent, biconjugate vaccines that can provide protective immunity, especially against vulnerable populations, can mitigate the effects of KP infections. In this review, we discuss the virulence mechanisms of KP and how it evades the innate host immunity, and the interplay between the virulence and immune evasion strategies. The progress in the search for a vaccine to protect against KP infections will also be highlighted.

scholarly journals New Perspectives on Antimicrobial Agents: Ceftolozane/tazobactam

2021 ◽  
Author(s):  
Bryan D. Lizza ◽  
Kevin D. Betthauser ◽  
David J. Ritchie ◽  
Scott T. Micek ◽  
Marin H. Kollef
Keyword(s):  
Antimicrobial Agents ◽  
Generation Cephalosporin ◽  
Multidrug Resistant ◽  
European Medicines Agency ◽  
Real World Data ◽  
Specific Patient ◽  
Previous Infection ◽  
Current Utilization ◽  
Tract Infections ◽  
Abdominal Infections

Ceftolozane-tazobactam (C/T) is a new fifth-generation cephalosporin/β-lactamase inhibitor combination approved by the Food and Drug Administration and the European Medicines Agency for treatment of complicated intra-abdominal infections, complicated urinary tract infections, and hospital-acquired pneumonia in adult patients. This review will briefly describe the pharmacology of C/T and focus on the emerging clinical trial and real-world data supporting its current utilization. Additionally, our synthesis of this data over time has set our current usage of C/T at Barnes-Jewish Hospital (BJH). C/T is primarily employed as directed monotherapy at BJH when P. aeruginosa isolates are identified with resistance to other beta-lactams. C/T can also be used empirically at BJH prior to microbiologic detection of an antibiotic-resistant P. aeruginosa isolate in specific clinical situations. These situations include critically ill patients in the ICU setting where there is a high likelihood of infection with multidrug-resistant (MDR) P. aeruginosa including patients failing therapy with a carbapenem, specific patient populations known to be at high risk for infection with MDR P. aeruginosa (e.g., lung transplant and cystic fibrosis patients), and patients know to have previous infection or colonization with MDR P. aeruginosa.

scholarly journals Food Safety through Natural Antimicrobials

Antibiotics ◽  
2019 ◽  
Vol 8 (4) ◽  
pp. 208 ◽  
Author(s):  
Emiliano J. Quinto ◽  
Irma Caro ◽  
Luz H. Villalobos-Delgado ◽  
Javier Mateo ◽  
Beatriz De-Mateo-Silleras ◽  
...  
Keyword(s):  
Food Safety ◽  
Food Industry ◽  
Antimicrobial Agents ◽  
Multidrug Resistant ◽  
Microbial Pathogens ◽  
Health Issues ◽  
Natural Antimicrobial ◽  
Natural Antimicrobials ◽  
Nutritional Values ◽  
Contaminated Food

Microbial pathogens are the cause of many foodborne diseases after the ingestion of contaminated food. Several preservation methods have been developed to assure microbial food safety, as well as nutritional values and sensory characteristics of food. However, the demand for natural antimicrobial agents is increasing due to consumers’ concern on health issues. Moreover, the use of antibiotics is leading to multidrug resistant microorganisms reinforcing the focus of researchers and the food industry on natural antimicrobials. Natural antimicrobial compounds from plants, animals, bacteria, viruses, algae and mushrooms are covered. Finally, new perspectives from researchers in the field and the interest of the food industry in innovations are reviewed. These new approaches should be useful for controlling foodborne bacterial pathogens; furthermore, the shelf-life of food would be extended.

scholarly journals Virulence Potential and Treatment Options of Multidrug-Resistant (MDR) Acinetobacter baumannii

2021 ◽  
Vol 9 (10) ◽  
pp. 2104
Author(s):  
Sunil Kumar ◽  
Razique Anwer ◽  
Arezki Azzi
Keyword(s):  
Acinetobacter Baumannii ◽  
Virulence Factors ◽  
Bacterial Infections ◽  
Antimicrobial Agents ◽  
Treatment Options ◽  
Outer Membrane Proteins ◽  
Multidrug Resistant ◽  
High Rate ◽  
World Health ◽  
Tract Infections

Acinetobacter baumannii is an opportunistic pathogen which is undoubtedly known for a high rate of morbidity and mortality in hospital-acquired infections. A. baumannii causes life-threatening infections, including; ventilator-associated pneumonia (VAP), meningitis, bacteremia, and wound and urinary tract infections (UTI). In 2017, the World Health Organization listed A. baumannii as a priority-1 pathogen. The prevalence of A. baumannii infections and outbreaks emphasizes the direct need for the use of effective therapeutic agents for treating such infections. Available antimicrobials, such as; carbapenems, tigecycline, and colistins have insufficient effectiveness due to the appearance of multidrug-resistant strains, accentuating the need for alternative and novel therapeutic remedies. To understand and overcome this menace, the knowledge of recent discoveries on the virulence factors of A. baumannii is needed. Herein, we summarized the role of various virulence factors, including; outer membrane proteins, efflux pumps, biofilm, penicillin-binding proteins, and siderophores/iron acquisition systems. We reviewed the recent scientific literature on different A. baumannii virulence factors and the effective antimicrobial agents for the treatment and management of bacterial infections.

scholarly journals Antimicrobial-Resistant Pathogens Associated with Healthcare-Associated Infections Summary of Data Reported to the National Healthcare Safety Network at the Centers for Disease Control and Prevention, 2009–2010

2013 ◽  
Vol 34 (1) ◽  
pp. 1-14 ◽  
Author(s):  
Dawn M. Sievert ◽  
Philip Ricks ◽  
Jonathan R. Edwards ◽  
Amy Schneider ◽  
Jean Patel ◽  
...  
Keyword(s):  
Antimicrobial Agents ◽  
Klebsiella Oxytoca ◽  
Multidrug Resistant ◽  
Healthcare Associated Infections ◽  
Gram Negative ◽  
E Coli ◽  
National Healthcare ◽  
National Healthcare Safety Network ◽  
Tract Infections ◽  
Healthcare Associated

Objective.To describe antimicrobial resistance patterns for healthcare-associated infections (HAIs) reported to the National Healthcare Safety Network (NHSN) during 2009-2010.Methods.Central line-associated bloodstream infections, catheter-associated urinary tract infections, ventilator-associated pneumonia, and surgical site infections were included. Pooled mean proportions of isolates interpreted as resistant (or, in some cases, nonsusceptible) to selected antimicrobial agents were calculated by type of HAI and compared to historical data.Results.Overall, 2,039 hospitals reported 1 or more HAIs; 1,749 (86%) were general acute care hospitals, and 1,143 (56%) had fewer than 200 beds. There were 69,475 HAIs and 81,139 pathogens reported. Eight pathogen groups accounted for about 80% of reported pathogens: Staphylococcus aureus (16%), Enterococcus spp. (14%), Escherichia coli (12%), coagulase-negative staphylococci (11%), Candida spp. (9%), Klebsiella pneumoniae (and Klebsiella oxytoca; 8%), Pseudomonas aeruginosa (8%), and Enterobacter spp. (5%). The percentage of resistance was similar to that reported in the previous 2-year period, with a slight decrease in the percentage of S. aureus resistant to oxacillins (MRSA). Nearly 20% of pathogens reported from all HAIs were the following multidrug-resistant phenotypes: MRSA (8.5%); vancomycin-resistant Enterococcus (3%); extended-spectrum cephalosporin-resistant K. pneumoniae and K. oxytoca (2%), E. coli (2%), and Enterobacter spp. (2%); and carbapenem-resistant P. aeruginosa (2%), K. pneumoniae/oxytoca (<1%), E, coli (<1%), and Enterobacter spp. (<1%). Among facilities reporting HAIs with 1 of the above gram-negative bacteria, 20%-40% reported at least 1 with the resistant phenotype.Conclusion.While the proportion of resistant isolates did not substantially change from that in the previous 2 years, multidrug-resistant gram-negative phenotypes were reported from a moderate proportion of facilities.

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