An Overview of the Activities of Cefiderocol Against Sensitive and Multidrug- Resistant (MDR) Bacteria

2020 ◽  
Vol 20 (18) ◽  
pp. 1908-1916
Author(s):  
Manaf AlMatar ◽  
Osman Albarri ◽  
Essam A. Makky ◽  
Işıl Var ◽  
Fatih Köksal
Keyword(s):  
Multidrug Resistant ◽  
Therapeutic Agents ◽  
Health Concern ◽  
Side Chain ◽  
Gram Negative Bacteria ◽  
Drug Resistant ◽  
Public Health Concern ◽  
Gram Negative ◽  
Penicillin Binding Proteins ◽  
The Public

The need for new therapeutics and drug delivery systems has become necessary owing to the public health concern associated with the emergence of multidrug-resistant microorganisms. Among the newly discovered therapeutic agents is cefiderocol, which was discovered by Shionogi Company, Japan as an injectable siderophore cephalosporin. Just like the other β-lactam antibiotics, cefiderocol exhibits antibacterial activity via cell wall synthesis inhibition, especially in Gram negative bacteria (GNB); it binds to the penicillin-binding proteins, but its unique attribute is that it crosses the periplasmic space of bacteria owing to its siderophore-like attribute; it also resists the activity of β-lactamases. Among all the synthesized compounds with the modified C-7 side chain, cefiderocol (3) presented the best and well-balanced activity against multi-drug resistant (MDR) Gram negative bacteria, including those that are resistant to carbapenem. İn this article, an overview of the recent studies on cefiderocol was presented.

scholarly journals Super-Cationic Peptide Dendrimers—Synthesis and Evaluation as Antimicrobial Agents

Antibiotics ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 695
Author(s):  
Estelle J. Ramchuran ◽  
Isabel Pérez-Guillén ◽  
Linda A. Bester ◽  
René Khan ◽  
Fernando Albericio ◽  
...  
Keyword(s):  
Antibacterial Agent ◽  
Antimicrobial Agents ◽  
Health Concern ◽  
Gram Negative Bacteria ◽  
Cationic Peptide ◽  
Public Health Concern ◽  
Gram Negative ◽  
Peptide Dendrimers ◽  
Microbial Infections ◽  
Lead Candidate

Microbial infections are a major public health concern. Antimicrobial peptides (AMPs) have been demonstrated to be a plausible alternative to the current arsenal of drugs that has become inefficient due to multidrug resistance. Herein we describe a new AMP family, namely the super-cationic peptide dendrimers (SCPDs). Although all members of the series exert some antibacterial activity, we propose that special attention should be given to (KLK)2KLLKLL-NH2 (G1KLK-L2KL2), which shows selectivity for Gram-negative bacteria and virtually no cytotoxicity in HepG2 and HEK293. These results reinforce the validity of the SCPD family as a valuable class of AMP and support G1KLK-L2KL2 as a strong lead candidate for the future development of an antibacterial agent against Gram-negative bacteria.

scholarly journals Curative Treatment of Severe Gram-Negative Bacterial Infections by a New Class of Antibiotics Targeting LpxC

mBio ◽  
2017 ◽  
Vol 8 (4) ◽  
Author(s):  
Nadine Lemaître ◽  
Xiaofei Liang ◽  
Javaria Najeeb ◽  
Chul-Jin Lee ◽  
Marie Titecat ◽  
...  
Keyword(s):  
Bacterial Infections ◽  
Biosynthetic Pathway ◽  
Lipid A ◽  
Multidrug Resistant ◽  
Gram Negative Bacteria ◽  
Drug Resistant ◽  
Bubonic Plague ◽  
Gram Negative ◽  
New Class

ABSTRACT The infectious diseases caused by multidrug-resistant bacteria pose serious threats to humankind. It has been suggested that an antibiotic targeting LpxC of the lipid A biosynthetic pathway in Gram-negative bacteria is a promising strategy for curing Gram-negative bacterial infections. However, experimental proof of this concept is lacking. Here, we describe our discovery and characterization of a biphenylacetylene-based inhibitor of LpxC, an essential enzyme in the biosynthesis of the lipid A component of the outer membrane of Gram-negative bacteria. The compound LPC-069 has no known adverse effects in mice and is effective in vitro against a broad panel of Gram-negative clinical isolates, including several multiresistant and extremely drug-resistant strains involved in nosocomial infections. Furthermore, LPC-069 is curative in a murine model of one of the most severe human diseases, bubonic plague, which is caused by the Gram-negative bacterium Yersinia pestis. Our results demonstrate the safety and efficacy of LpxC inhibitors as a new class of antibiotic against fatal infections caused by extremely virulent pathogens. The present findings also highlight the potential of LpxC inhibitors for clinical development as therapeutics for infections caused by multidrug-resistant bacteria. IMPORTANCE The rapid spread of antimicrobial resistance among Gram-negative bacilli highlights the urgent need for new antibiotics. Here, we describe a new class of antibiotics lacking cross-resistance with conventional antibiotics. The compounds inhibit LpxC, a key enzyme in the lipid A biosynthetic pathway in Gram-negative bacteria, and are active in vitro against a broad panel of clinical isolates of Gram-negative bacilli involved in nosocomial and community infections. The present study also constitutes the first demonstration of the curative treatment of bubonic plague by a novel, broad-spectrum antibiotic targeting LpxC. Hence, the data highlight the therapeutic potential of LpxC inhibitors against a wide variety of Gram-negative bacterial infections, including the most severe ones caused by Y. pestis and by multidrug-resistant and extensively drug-resistant carbapenemase-producing strains. IMPORTANCE The rapid spread of antimicrobial resistance among Gram-negative bacilli highlights the urgent need for new antibiotics. Here, we describe a new class of antibiotics lacking cross-resistance with conventional antibiotics. The compounds inhibit LpxC, a key enzyme in the lipid A biosynthetic pathway in Gram-negative bacteria, and are active in vitro against a broad panel of clinical isolates of Gram-negative bacilli involved in nosocomial and community infections. The present study also constitutes the first demonstration of the curative treatment of bubonic plague by a novel, broad-spectrum antibiotic targeting LpxC. Hence, the data highlight the therapeutic potential of LpxC inhibitors against a wide variety of Gram-negative bacterial infections, including the most severe ones caused by Y. pestis and by multidrug-resistant and extensively drug-resistant carbapenemase-producing strains.

scholarly journals Antimicrobial Resistance in Hospitalized Surgical Patients: a Silently Emerging Public Health Concern in Benin.

2020 ◽  
Author(s):  
Carine Laurence YEHOUENOU ◽  
Arsène A. KPANGON ◽  
Dissou AFFOLABI ◽  
Hector RODRIGUEZ-VILLALOBOS ◽  
Françoise Van Bambeke ◽  
...  
Keyword(s):  
Gastrointestinal Surgery ◽  
Surgical Site Infections ◽  
Multidrug Resistant ◽  
Public Hospitals ◽  
Health Concern ◽  
Diffusion Method ◽  
Resistant Bacteria ◽  
Gram Negative Bacteria ◽  
Strict Adherence ◽  
Gram Negative

Abstract Background: Surgical site infections are related to high morbidity, mortality and healthcare costs. As the emergence of multidrug-resistant bacterial pathogens in hospitals is becoming a worldwide challenge for surgeons who treat healthcare-associated infections, we wished to identify the causative agents involved in surgical site infections and their susceptibility pattern in six public hospitals in Benin. Methods: Using standard microbiological procedures, we processed pus specimens collected from obstetrics and gastrointestinal surgery wards. Mass spectrometry (MALDI-TOF) was used for confirmation. The antibiotic susceptibility test firstly used the Kirby-Bauer disc diffusion method. The secondary test by microdilution used the Beckton Dickinson Phoenix automated system (Becton Dickinson Diagnostic, USA). Results: We included 304 patients (mean age 32 ± 11 years), whose median length of stay was 9 days. A total of 259 wound swabs (85.2%) had positive aerobic bacterial growth. In obstetrics S. aureus (28.5%, n=42) was the most common isolate. In contrast, Gram-negative bacteria (GNB) were predominant in gastrointestinal surgery. The most dominant being E.coli (38.4%, n=31). Overall, 90.8% (n=208) of aerobic bacteria were multidrug resistant. Two-third of S. aureus (65.3%, n= 32) were methicillin-resistant Staphylococcus aureus (MRSA), three of which carried both MRSA and induced clindamycin resistance (ICR). GNB showed high resistance to ceftazidime, ceftriaxone and cefepime. Extended-spectrum beta-lactamases were presented by 69.4% of E.coli (n=43/62) and 83.3% of K. pneumoniae (n=25/30). Overall, twelve Gram negative bacteria (5.24%) isolates showed resistance to at least one carbapenem. No isolates showed a wild-type susceptible phenotype.Conclusion: This study shows the alarming prevalence of multidrug resistant organisms from surgical site infections in Benin hospitals. To reduce the spread of these multidrug-resistant bacteria, periodic surveillance of surgical site infections and strict adherence to good hand-hygiene practice are essential.

scholarly journals Phenotypic characterization of carbapenem non-susceptible gram-negative bacilli isolated from clinical specimens

PLoS ONE ◽  
2021 ◽  
Vol 16 (12) ◽  
pp. e0256556
Author(s):  
Abera Abdeta ◽  
Adane Bitew ◽  
Surafel Fentaw ◽  
Estifanos Tsige ◽  
Dawit Assefa ◽  
...  
Keyword(s):  
Public Health ◽  
Prevention And Control ◽  
Multidrug Resistant ◽  
Gram Negative Bacteria ◽  
Drug Resistant ◽  
Gram Negative ◽  
Extensively Drug Resistant ◽  
Gram Negative Organisms ◽  
And Control ◽  
Public Health Institute

Background Multidrug resistant, extremely drug-resistant, pan-drug resistant, carbapenem-resistant, and carbapenemase-producing gram-negative bacteria are becoming more common in health care settings and are posing a growing threat to public health. Objective The study was aimed to detect and phenotypically characterize carbapenem no- susceptible gram-negative bacilli at the Ethiopian Public Health Institute. Materials and methods A prospective cross-sectional study was conducted from June 30, 2019, to May 30, 2020, at the national reference laboratory of the Ethiopian Public Health Institute. Clinical samples were collected, inoculated, and incubated for each sample in accordance with standard protocol. Antimicrobial susceptibility testing was conducted using Kirby-Bauer disk diffusion method. Identification was done using the traditional biochemical method. Multidrug-resistant and extensively drug-resistant isolates were classified using a standardized definition established by the European Centre for Disease Prevention and Control and the United States Centers for Disease Prevention and Control. Gram-negative organisms with reduced susceptibility to carbapenem antibiotics were considered candidate carbapenemase producers and subjected to modified carbapenem inactivation and simplified carbapenem inactivation methods. Meropenem with EDTA was used to differentiate metallo-β-lactamase (MBL) from serine carbapenemase. Meropenem (MRP)/meropenem + phenylboronic acid (MBO) were used to differentiate Klebsiella pneumoniae carbapenemase (KPC) from other serine carbapenemase producing gram-negative organisms. Results A total of 1,337 clinical specimens were analyzed, of which 429 gram-negative bacterial isolates were recovered. Out of 429 isolates, 319, 74, and 36 were Enterobacterales, Acinetobacter species, and Pseudomonas aeruginosa respectively. In our study, the prevalence of multidrug-resistant, extensively drug-resistant, carbapenemase-producing, and carbapenem nonsusceptible gram-negative bacilli were 45.2%, 7.7%, 5.4%, and 15.4% respectively. Out of 429 isolates, 66 demonstrated reduced susceptibility to the antibiotics meropenem and imipenem. These isolates were tested for carbapenemase production of which 34.8% (23/66) were carbapenemase producers. Out of 23 carbapenemase positive gram-negative bacteria, ten (10) and thirteen (13) were metallo-beta-lactamase and serine carbapenemase respectively. Three of 13 serine carbapenemase positive organisms were Klebsiella pneumoniae carbapenemase. Conclusion This study revealed an alarming level of antimicrobial resistance (AMR), with a high prevalence of multidrug-resistant (MDR) and extremely drug-resistant, carbapenemase-producing gram-negative bacteria, particularly among intensive care unit patients at the health facility level. These findings point to a scenario in which clinical management of infected patients becomes increasingly difficult and necessitates the use of “last-resort” antimicrobials likely exacerbating the magnitude of the global AMR crisis. This mandates robust AMR monitoring and an infection prevention and control program.

scholarly journals Investigating colistin drug resistance: The role of high-throughput sequencing and bioinformatics

F1000Research ◽  
2019 ◽  
Vol 8 ◽  
pp. 150 ◽  
Author(s):  
Dickson Aruhomukama ◽  
Ivan Sserwadda ◽  
Gerald Mboowa
Keyword(s):  
Antibiotic Resistance ◽  
High Throughput ◽  
Bacterial Infections ◽  
High Throughput Sequencing ◽  
Health Concern ◽  
Gram Negative Bacteria ◽  
Drug Resistant ◽  
Colistin Resistance ◽  
Gram Negative

Bacterial infections involving antibiotic resistant gram-negative bacteria continue to increase and represent a major global public health concern. Resistance to antibiotics in these bacteria is mediated by chromosomal and/or acquired resistance mechanisms, these give rise to multi-drug resistant (MDR) or extensive drug resistant (XDR) bacterial strains. Most recently, a novel acquired plasmid mediated resistance mechanism to colistin, an antibiotic that had been set apart as the last resort antibiotic in the treatment of infections involving MDR and XDR gram-negative bacteria, has been reported. Plasmid mediated colistin resistant gram-negative bacteria have been described to be pan-drug resistant, implying a state devoid of alternative antibiotic therapeutic options. This review describes the evolution of antibiotic resistance to plasmid mediated colistin resistance, and discusses the potential role of high-throughput sequencing technologies, genomics and bioinformatics towards improving antibiotic resistance surveillance, the search for novel drug targets and precision antibiotic therapy focused at combating colistin resistance, and antimicrobial resistance as a whole.

scholarly journals High Prevalence of Antimicrobial Resistance among Gram Negative Bacteria Isolated from Poultry

10.3823/824 ◽  
2018 ◽  
Vol 8 (3) ◽  
Author(s):  
Abdelraouf A Elmanama ◽  
Mariam Raed Al-Reefi ◽  
Mohammed A. Albayoumi ◽  
Alaa M. Marouf ◽  
Islam F. Hassona
Keyword(s):  
Carbapenem Resistance ◽  
Multidrug Resistant ◽  
Hospital Environment ◽  
Health Concern ◽  
Resistance Pattern ◽  
Resistant Bacteria ◽  
Gram Negative Bacteria ◽  
Salmonella Spp ◽  
Isolation And Identification ◽  
Gram Negative

Background: Multidrug resistant bacteria (MDR), such as Escherichia coli and Salmonella spp. are threat to the human health care system. In recent years, these MDR bacteria have been found increasingly inside and outside the hospital environment. Food animals (meat and poultry) are increasingly colonized with MDR bacteria, thus posing an additional concern. This study is intended to determine susceptibility and resistance pattern of pathogenic Gram negative bacteria isolated from rectal swabs of chicken against 16 antibiotics. Methods: A total of 216 cloacal swab samples (Gaza strip poultry farms) and 87 frozen and fresh meat samples (from slaughter houses and retails) from June 2017 to June 2018 were collected. Isolation and identification of organisms were achieved using standard bacteriological techniques. Antimicrobial susceptibility test was performed according to standard protocols. Results: 360 Enterobacteriaceae isolates, and 56 Gram-negative non fermenter were recovered. The predominant Enterobacteriaceae isolate was Citrobacter spp. (22.6%), followed by Enterobacter spp. (17.6%) and E. coli (16.5%). High rates of resistance against Ampicillin (85.4%) and Trimethoprim/ Sulfamethoxazole (80.1%) followed by Chloramphenicol (74%) were recorded. Six samples were positive for Salmonella spp. and Shigella spp. Of the tested Enterobacteriacae isolates, 94.7% were multidrug resistant (MDR), and 31.4% of  None fermenting bacilli (NFB) were MDR. Carbapenem resistance was found to be high among isolates; 51.9% for imipenem and 1.8% for meropenem. Conclusion: Isolated bacteria in the study area were MDR and this suggests that chickens may be important reservoir of antimicrobial resistant organisms which is a major public health concern.    

scholarly journals CO-PRODUCTION OF EXTENDED-SPECTRUM BETA-LACTAMASES AND METALLO BETA-LACTAMASES AMONG MULTI-DRUG RESISTANT GRAM-NEGATIVE BACTERIA ISOLATES COLLECTED FROM TERTIARY HOSPITALS IN OYO STATE, NIGERIA

2020 ◽  
Vol 4 (3) ◽  
pp. 230-241
Author(s):  
Olumuyiwa Alabi ◽  
Abiola Obisesan ◽  
Mary Taiwo ◽  
Rhoda Adewuyi
Keyword(s):  
Phylogenetic Tree ◽  
Health Concern ◽  
Gram Negative Bacteria ◽  
Drug Resistant ◽  
Disc Diffusion ◽  
Gram Negative ◽  
Beta Lactamases ◽  
Extended Spectrum ◽  
Extended Spectrum Beta Lactamases ◽  
Tertiary Hospitals

Extended-spectrum beta-lactamases (ESBLs) and metallo beta-lactamases (MBLs) are compromising the chemotherapeutic use of cephalosporins and carbapenems respectively. This study investigated the burden of ESBLs and MBLs co-production among multi-drug resistant (MDR) Gram-negative bacteria collected from two tertiary hospitals in Oyo State. A total of 240 non-duplicated clinical isolates of Escherichia coli, Klebsiella spp. and Pseudomonas spp. were collected from the Microbiology units of two tertiary hospitals in Oyo State and their identities authenticated using standard identification techniques. Antimicrobial susceptibility testing was carried out by disc-diffusion method and isolates exhibiting resistance to ≥3 classes of antibiotics selected as MDR strains. ESBL and MBL production was detected by double-disc synergy test (DDST) and combined-disc-diffusion test (CDDT) respectively. Selected beta-lactamase genes were detected by PCR, amplicons sent out for sequencing and phylogenetic tree of the sequences constructed using Mega X software. MDR was exhibited by 43.8% of the isolates. ESBLs and MBLs were produced by 32.4% and 7.6% of the MDR isolates respectively. Co-production of ESBL and MBL was observed in 6.7% of the MDR isolates. BlaCTX-M-15 (67.7%), blaTEM-1 (55.9%), blaSHV-1 (47.1%), co-existing blaTEM + blaSHV, blaTEM + blaCTX-M, blaCTX-M + blaSHV (each in 5.9%) and blaCTX-M +blaTEM + blaSHV (26.5%) were detected among the ESBL-producers. MBL genes were not detected among the MBL-producers. Only blaTEM-1 sequences showed two different claudes on the phylogenetic tree. The occurrence of MDR isolates co-harbouring different classes of beta-lactamse genes observed in this study is of public health concern and hence, requires stricter control of antibiotic use.

scholarly journals Multidrug resistant, extensively drug resistant and pan drug resistant gram negative bacteria at a tertiary care centre in Bhubaneswar

2019 ◽  
Vol 6 (2) ◽  
pp. 567 ◽  
Author(s):  
Dipti Pattnaik ◽  
Subhra Snigdha Panda ◽  
Nipa Singh ◽  
Smrutilata Sahoo ◽  
Ipsa Mohapatra ◽  
...  
Keyword(s):  
Tertiary Care ◽  
Multidrug Resistant ◽  
Diffusion Method ◽  
Gram Negative Bacteria ◽  
Drug Resistant ◽  
Gram Negative ◽  
Extensively Drug Resistant ◽  
Resistant Strains ◽  
Drug Resistant Strains ◽  
Esbl Producers

Background: Multidrug resistance has emerged as a challenge in health care settings. Again increasing prevalence of multidrug resistant (MDR), extensively drug resistant (XDR) and pan drug resistant (PDR) gram negative bacteria is making the condition more critical because of limited options of antibiotics, increasing morbidity, mortality and hospital stay of the patients. The present study is carried out with an aim to estimate the prevalence of MDR, XDR, PDR gram negative bacteria in a tertiary care hospital.Methods: Total of 912 gram negative bacterial isolates obtained from various samples of indoor patients in a tertiary care hospital, were studied over a period of six months. The bacteria were identified by conventional methods. Antibiotic sensitivity testing was done by Kirby Bauer disc diffusion method. Minimum inhibitory concentration (MIC) of antibiotics for the resistant isolates were detected by Vitek-2 automated method. MDR, XDR and PDR were determined according to the definitions suggested by European Centre for Disease Prevention and Control (ECDC), and Centers for Disease Control and Prevention (CDC). Prevalence of extended spectrum beta lactamase (ESBL) producers was estimated.Results: Out of 912 isolates, prevalence of MDR, XDR and PDR were 66.12%, 34.32% and 0.98% respectively. Prevalence of MDR and XDR were higher in ICUs than clinical wards (p<0.0001). Prevalence of ESBL producers was 48.4%.Conclusions: The study highlights increased prevalence of multidrug resistant and extensively drug resistant strains in our hospital. Stringent surveillance, proper implementation of hospital infection control practices and antimicrobial stewardship will help in limiting the emergence and spread of drug resistant strains.

scholarly journals Detection and phenotypic characterization of carbapenem non susceptible gram-negative bacilli isolated from clinical specimens

2021 ◽  
Author(s):  
Abera Abdeta ◽  
Adane Bitew ◽  
Surafel Fentaw ◽  
Estifanos Tsige ◽  
Dawit Assefa ◽  
...  
Keyword(s):  
Public Health ◽  
Prevention And Control ◽  
Multidrug Resistant ◽  
Gram Negative Bacteria ◽  
Drug Resistant ◽  
Gram Negative ◽  
Clinical Specimens ◽  
Extensively Drug Resistant ◽  
And Control ◽  
Public Health Institute

Background Multi-drug resistant, extremely drug-resistant, pan-drug resistant, carbapenem-resistant, and carbapenemase-producing gram-negative bacteria are becoming more common in health care settings and are posing a growing threat to public health. Objective The study was aimed to determine the magnitude of multi-drug resistant, extremely drug-resistant, carbapenem non-susceptible, and carbapenemase-producing gram-negative bacilli at Ethiopian Public Health Institute. Materials and methods Prospective cross-sectional study was conducted from June 30, 2019, to May 30, 2020, at the national reference laboratory of the Ethiopian Public Health Institute. Clinical samples were collected, inoculated, and incubated in accordance to standard protocol for each sample. Antimicrobial susceptibility testing was done using Kirby Bauer disk diffusion. Identification was done using the traditional biochemical method. Multidrug-resistant and extensively drug-resistant were classified using a standardized definition established by European Centers for Disease prevention and control and the United States Centers for Disease prevention and control experts. Carbapenemase production was confirmed by modified carbapenem inactivation and a simplified carbapenem inactivation method. Meropenem with EDTA was used to differentiate serine carbapenemase and Metallo β-lactamase. Results A total of 1337 clinical specimens were analyzed, of which 429-gram negative bacilli isolates were recovered. Out of 429 isolates 319, 74, and 36 were Enterobacterales, Acinetobacter species, and P. aeruginosa respectively. In our study, the prevalence of Multidrug-resistant, extensively drug-resistant, Carbapenemase-producing, and carbapenem non-susceptible Gram-negative bacilli were, 45.2%, 7.7%, 5.4%, and 15.4% respectively. Out of 66 isolates screened for Carbapenemase, 34.8% (23/66) were Carbapenemase enzyme producers. Ten out of twenty-three Carbapenemase-positive organisms were Metallo-beta-lactamase producers. Thirteen out of twenty-three isolates were serine carbapenemase producers. Three out of 13 serine Carbapenemase positive organisms were Klebsiella pneumoniae Carbapenemase. Conclusion The finding from this study revealed a high prevalence of Multidrug-resistant, extremely drug-resistant, carbapenemase-producing gram-negative bacteria, particularly among Intensive care unit patients at the health facility level, this necessitates a robust laboratory-based antimicrobial resistance monitoring and infection prevention and control program.

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