Lower respiratory Tract Infection (LRTI) is one of the fourth most common cause of mortality across the globe, and constitutes to be a major portion in critically ill patients associated with ...prolonged hospitalisation. Apart from age factor, other risk factors which predispose to the LRTI include poor sanitization, severe malnutrition, and lack of breast feeding for infants, HIV infection, lack of immunization, chronic illness, family history of LRTI and exposure to tobacco smoke/air pollutants.
The third generation cephalosporins are used in management and treatment of gram-negative and gram-positive organism. Common bacteria implicated in these infections include
S. pneumoniae,
H. influenzae,
Chlamydia pneumoniae, and
Staphylococcus aureus. Third generation cephalosporins also target respiratory ailments like acute bronchitis, pneumonia, acute exacerbation of chronic lung diseases (such as COPD or bronchiectasis). Cefotaxime and ceftriaxone have been widely recommended in guidelines to be used for many infections and diseases, but, some serious adverse effects have been seen in past few years with ceftriaxone like cholelithiasis, encephalopathy, memory impairment, tonic- clonic seizures, neurotoxicity and auto-immune haemolytic anaemia. This fact compels us to revisit the clinically safer and efficacious drug Cefotaxime which have been used since decades but have not developed any resistance till date. Cefotaxime has been found to be well tolerated and not associated with hypo-prothrombinemia/coagulopathies, disulfiram-like reactions, as with other cephalosporins. It can readily cross the blood-brain barrier when administered intravenously and may treat gram-negative infections resistant to previous generations of cephalosporins.
Cefotaxime, demonstrates good efficacy and safety in the management of LRTIs including CAP, hospital acquired/nosocomial acquired pneumonia, acute exacerbation of pneumonia and acute bronchitis caused by both gram positive as well as gram negative bacteria.
Keywords: LRTI, Cefotaxime, cephalosporins, CAP, pneumonia, respiratory tract
Urinary tract infection (UTI) is one of the most prevalent infectious diseases with worldwide health threatening. Antimicrobial resistant strains of Escherichia coli (E. coli) are a common cause of ...UTI which were identified as a treatment challenge. This study aimed to assay the prevalence of common β-lactam resistance genes including bla
, bla
, bla
and bla
and phenotypic resistance to commonly used β-lactam and fluoroquinolone antibiotics in UTIs. These factors were evaluated in various phylogenetic groups (phylotypes) of E. coli isolates. Real-time PCR was applied to detect β-lactam resistance genes and conventional PCR was used to determine the phylotypes. Phenotypic resistance against β-lactams (ceftazidime, cefotaxime, aztreonam and ceftriaxone) and fluoroquinolones (ciprofloxacin) were identified by the disc diffusion technique. The ability of extended spectrum β-lactamases (ESBLs) production in E. coli isolates was detected using the combined disc diffusion method.
The prevalence of resistance genes were 89.6% for bla
, 44.3% for bla
, 6.6% for bla
and 0.9% for bla
. The two high prevalent phylotypes were B2 (29.2%) and D (17.9%) followed by E (14.1%), F (9.4%), C (6.6%) and 10.3% of isolates were unknown in phylotyping. Disc diffusion results showed high prevalence of antibiotic resistance to cefotaxime (88.6%), aztreonam (83%), ceftireaxon (77.3%), ceftazidime (76.4%) and ciprofloxacin (55.6%). Totally, 52.8% of isolates were found as phenotypical ESBL-producers.
This study's results confirmed an explosion of antibiotic resistance amongst E. coli isolates from UTI against β-lactams and fluoroquinolones. Findings explain the necessity of deep changes in quantity and quality of drug resistance diagnosis and antibiotic therapy strategies. More studies are suggested to better and confident evaluations.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
•Prevalence of ESBL/pAmpC-producing E. coli is highest in chicken meat.•Characteristics of isolates from turkey meat are significantly different to those from chicken.•Prevalence of CTX-M group among ...the ESBL/pAmpC producing E. coli isolates was highest in turkey (26.0%) and chicken (24.0 %).•Minced meat from beef or pork is contaminated at higher frequency than beef or pork.•Vegetables are contaminated only at a very low level in Germany.
The spread of extended-spectrum β-lactamases (ESBLs) in Escherichia coli is a major public health issue and ESBL-producing bacteria are frequently reported in livestock. For the assessment of the role of the foodborne transmission pathway in Germany, detailed data on the prevalence and characteristics of isolates of food origin are necessary. The objective of this study was to describe the prevalence of cefotaxime resistant E. coli as well as ESBL/pAmpC-producing E. coli and their characteristics in foods in Germany.
Out of 2256 food samples, the highest prevalence of cefotaxime resistant E. coli was observed in chicken meat (74.9%), followed by turkey meat (40.1%). Prevalence in beef, pork and minced meat was considerably lower (4.2–15.3%). Whereas 18.0% of the raw milk samples, collected at farm level were positive, this was true only for few cheese samples (1.3%). In one out of 399 vegetable samples a cefotaxime-resistant E. coli was isolated.
ESBL resistance genes of the CTX-M-group (10.1% of all samples) were most frequently detected, followed by genes of the pAmpC (2.6%), SHV (2.0%) and TEM (0.8%) families. Distribution of ESBL/AmpC-encoding E. coli resistance genes and E. coli phylogroups was significantly different between the chicken related food samples and all other food items.
Our study results reflect that consumers might get exposed to ESBL/pAmpC-producing E. coli through several food chains. These results together with those collected at primary production and in the human population in other studies will allow more detailed analysis of the foodborne pathways, considering transmission from livestock populations to food at retail and to consumers in Germany.
Here, we present a large (n = 107,207) genome-wide association study (GWAS) of general cognitive ability (“g”), further enhanced by combining results with a large-scale GWAS of educational ...attainment. We identified 70 independent genomic loci associated with general cognitive ability. Results showed significant enrichment for genes causing Mendelian disorders with an intellectual disability phenotype. Competitive pathway analysis implicated the biological processes of neurogenesis and synaptic regulation, as well as the gene targets of two pharmacologic agents: cinnarizine, a T-type calcium channel blocker, and LY97241, a potassium channel inhibitor. Transcriptome-wide and epigenome-wide analysis revealed that the implicated loci were enriched for genes expressed across all brain regions (most strongly in the cerebellum). Enrichment was exclusive to genes expressed in neurons but not oligodendrocytes or astrocytes. Finally, we report genetic correlations between cognitive ability and disparate phenotypes including psychiatric disorders, several autoimmune disorders, longevity, and maternal age at first birth.
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•Large-scale GWAS of cognitive performance, combined with GWAS of educational attainment•70 independent genomic loci associated with individual differences in cognition•Implicated genes suggest potential treatment targets for cognitive enhancement•Genetic overlap between cognitive ability and multiple health-related phenotypes
Lam et al. conduct a large-scale genome-wide association study of cognitive ability, identifying 70 associated loci. Results provide biological insights into the molecular basis of individual differences in cognitive ability, as well as their relationship to psychiatric and other health-relevant phenotypes.
Since antibiotic resistance is a major threat to global health, recent observations that the traditional test of minimum inhibitory concentration (MIC) is not informative enough to guide effective ...antibiotic treatment are alarming. Bacterial heteroresistance, in which seemingly susceptible isogenic bacterial populations contain resistant sub-populations, underlies much of this challenge. To close this gap, here we developed a droplet-based digital MIC screen that constitutes a practical analytical platform for quantifying the single-cell distribution of phenotypic responses to antibiotics, as well as for measuring inoculum effect with high accuracy. We found that antibiotic efficacy is determined by the amount of antibiotic used per bacterial colony forming unit (CFU), not by the absolute antibiotic concentration, as shown by the treatment of beta-lactamase-carrying Escherichia coli with cefotaxime. We also noted that cells exhibited a pronounced clustering phenotype when exposed to near-inhibitory amounts of cefotaxime. Overall, our method facilitates research into the interplay between heteroresistance and antibiotic efficacy, as well as research into the origin and stimulation of heterogeneity by exposure to antibiotics. Due to the absolute bacteria quantification in this digital assay, our method provides a platform for developing reference MIC assays that are robust against inoculum-density variations.
Antibiotic resistance is a major challenge to global public health. Discovery of new antibiotics is slow and to ensure proper treatment of bacterial infections new strategies are needed. One way to ...curb the development of antibiotic resistance is to design drug combinations where the development of resistance against one drug leads to collateral sensitivity to the other drug. Here we study collateral sensitivity patterns of the globally distributed extended-spectrum β-lactamase CTX-M-15, and find three non-synonymous mutations with increased resistance against mecillinam or piperacillin-tazobactam that simultaneously confer full susceptibility to several cephalosporin drugs. We show in vitro and in mice that a combination of mecillinam and cefotaxime eliminates both wild-type and resistant CTX-M-15. Our results indicate that mecillinam and cefotaxime in combination constrain resistance evolution of CTX-M-15, and illustrate how drug combinations can be rationally designed to limit the resistance evolution of horizontally transferred genes by exploiting collateral sensitivity patterns.
Carbapenems are "last resort" β-lactam antibiotics used to treat serious and life-threatening health care-associated infections caused by multidrug-resistant Gram-negative bacteria. Unfortunately, ...the worldwide spread of genes coding for carbapenemases among these bacteria is threatening these life-saving drugs. Metallo-β-lactamases (MβLs) are the largest family of carbapenemases. These are Zn(II)-dependent hydrolases that are active against almost all β-lactam antibiotics. Their catalytic mechanism and the features driving substrate specificity have been matter of intense debate. The active sites of MβLs are flanked by two loops, one of which, loop L3, was shown to adopt different conformations upon substrate or inhibitor binding, and thus are expected to play a role in substrate recognition. However, the sequence heterogeneity observed in this loop in different MβLs has limited the generalizations about its role. Here, we report the engineering of different loops within the scaffold of the clinically relevant carbapenemase NDM-1. We found that the loop sequence dictates its conformation in the unbound form of the enzyme, eliciting different degrees of active-site exposure. However, these structural changes have a minor impact on the substrate profile. Instead, we report that the loop conformation determines the protonation rate of key reaction intermediates accumulated during the hydrolysis of different β-lactams in all MβLs. This study demonstrates the existence of a direct link between the conformation of this loop and the mechanistic features of the enzyme, bringing to light an unexplored function of active-site loops on MβLs.
There is a rapid rise in the incidence of quinolone resistant bacteria in Nigeria. Most studies in Nigeria have focused on isolates from the clinical settings, with few focusing on isolates of ...environmental origin. This study aimed to investigate the antibiogram and carriage of plasmid-mediated quinolone resistance
(
PMQR) genes by quinolone-resistant isolates obtained from a pool of cefotaxime-resistant
Escherichia coli
(
E. coli
) recovered from sewage leaking out of some surface-leaking sanitary sewers in a University community in Nigeria. Isolation of
E. coli
from the sewage samples was done on CHROMagar
E. coli,
after enrichment of the samples was done in Brain Heart Infusion broth amended with 6 µg/mL of cefotaxime. Identification of presumptive
E. coli
was done using molecular methods (detection of
uidA
gene), while susceptibility to antibiotics was carried out using the disc diffusion method. Detection of PMQR genes (
qnrA
,
qnrB
,
qnrS
,
aac(6')-lb-cr
,
qepA
and
oqxAB
) was carried out using primer-specific PCR. A total of 32 non-repetitive cefotaxime-resistant
E. coli
were obtained from the sewage, with 21 being quinolone-resistant. The quinolone-resistant isolates showed varying level of resistance to the tested antibiotics, with imipenem being the only exception with 0% resistance. The PMQR genes:
aac(6')-lb-cr
,
qnrA
,
qnrB
,
qnrS
and
qepA
and
oqxAB
were detected in 90.5%, 61.9%, 47.6%, 38.1%, 4.8% and 0% respectively of the isolates. The findings of this study showed a high level of resistance to antibiotics and carriage of PMQR genes by quinolone-resistant
E. coli
obtained from the leaking sanitary sewers, suggesting a potential environmental and public health concern.
To test the synergistic effect of Cpl-711 endolysin and antibiotics for antipneumococcal activity.
A combination of Cpl-711 and different antibiotics (amoxicillin, cefotaxime, levofloxacin and ...vancomycin) was tested in a checkerboard assay against several multidrug-resistant Streptococcus pneumoniae strains. Mouse and zebrafish models of pneumococcal sepsis were used to confirm the in vitro data.
The activity of Cpl-711 combined with amoxicillin or cefotaxime was synergistic in the bactericidal effect against a serotype 23F multiresistant clinical isolate of S. pneumoniae. Synergy between Cpl-711 and cefotaxime was validated using both mouse and zebrafish models.
Combination of Cpl-711 and cefotaxime may help in the treatment of diseases caused by multiresistant pneumococcal strains.
HMOX1 has a dual role in cancers, especially involving chemoresistance. We demonstrate that cephalosporin antibiotics exert strong anticancer activity in nasopharyngeal carcinoma mainly via drastic ...upregulation of HMOX1.
Cephalosporin antibiotics are commonly used for the treatment or prophylaxis of bacterial infectious diseases in cancer patients. It is unknown whether they lead to chemoresistance in cancer patients, especially in nasopharyngeal carcinoma patients, who are being treated or required prophylaxis for an infectious syndrome with cephalosporin antibiotics.
MTT and clonogenic colony formation assays assessed the viability and proliferation of cultured cancer cells. Flow cytometry was used to detect apoptosis. Tumor growth was assessed using a xenograft model. Microarray and RT-qPCR expression analyses investigated differential gene expression.
Cefotaxime enhanced anticancer efficacy of cisplatin in nasopharyngeal carcinoma without enhancing the toxic side effects both
and
. However, cefotaxime significantly reduced the cytotoxicity of cisplatin in other cancer cell lines. Cefotaxime and cisplatin co-regulated 5 differential genes in CNE2 cells in a direction supporting the enhancement of anticancer efficacy, of which, THBS1 and LAPTM5 were further upregulated, STAG1, NCOA5, and PPP3CB were further downregulated. Out of the 18 apoptotic pathways significantly enriched in the combination group, THBS1 and HMOX1 overlapped in 14 and 12 pathways, respectively. Extrinsic apoptotic signaling pathway (GO: 2001236) was the only apoptotic pathway commonly enriched in cefotaxime group, cisplatin group and combination group, and THBS1 and HMOX1 were the overlapped genes of this pathway. THBS1 also overlapped in P53 signaling pathway and ECM-receptor interaction signaling pathway enriched by KEGG.
Cephalosporin antibiotics are chemosensitizers of conventional chemotherapeutic drugs in the chemotherapy of nasopharyngeal carcinoma, but they may lead to chemoresistance by cytoprotection in other cancers. Cefotaxime and cisplatin co-regulate THBS1, LAPTM5, STAG1, NCOA5 and PPP3CB suggesting their involvement in the enhancement of anticancer efficacy in nasopharyngeal carcinoma. Targeting of P53 signaling pathway and ECM-receptor interaction signaling pathway was correlated to the enhancement. With additional benefit for treatment or prophylaxis of an infectious syndrome, cephalosporin antibiotics can benefit the therapy of nasopharyngeal carcinoma either as anticancer agents or as chemosensitizers of chemotherapeutic drugs in combination chemotherapy.
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