SciCombinator

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Concept: Cephalosporin

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Among 390 Escherichia coli and Klebsiella pneumoniae clinical isolates collected during 2014-2015 displaying colistin MIC values ≥4 μg/ml, 19 (4.9%) carried mcr-1 These isolates were all E. coli collected in ten countries, including the United States. Most isolates were susceptible to cephalosporins and were all susceptible to carbapenems, amikacin, tigecyline and ceftazidime-avibactam among other agents. Data from this global surveillance program expand the knowledge on the occurrence of mcr-1-carrying isolates.

Concepts: United States, Escherichia coli, Enterobacteriaceae, Escherichia, Proteobacteria, Beta-lactamase, Enterobacteria, Cephalosporin

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Background. CDC guidelines for pharyngeal gonorrhea treatment recommend dual therapy with intramuscular ceftriaxone and either azithromycin or doxycycline. Few clinical data exist to support this recommendation.Methods. We conducted a retrospective analysis of patients diagnosed with pharyngeal gonorrhea, 1993-2011, at a sexually transmitted disease clinic in Seattle, WA, and compared the proportion of repeat positive tests for pharyngeal gonorrhea 7-180 days following treatment among persons receiving different drug regimens. Associations of treatment regimens were assessed using relative risks through Poisson regression models with log link and robust standard errors.Results. A total of 1,440 cases of pharyngeal gonorrhea were diagnosed during the study period, 25% of which (N=360) underwent retesting. Among retested patients, the risk of repeat positive test was lowest among persons receiving an oral cephalosporin and azithromycin (7%, referent group), and highest among those receiving an oral cephalosporin alone (30%; RR 3.98, 95% CI 1.70 - 9.36) or in combination with doxycycline (33%; RR 4.18, 95% CI 1.64 - 10.7). The risk of repeat test positivity did not significantly differ between persons treated with an oral cephalosporin and azithromycin and those treated with ceftriaxone alone (9.1%; RR 0.81, 95% CI 0.18 - 3.60) or ceftriaxone combined with azithromycin or doxycycline (11.3%; RR 1.20, 95% CI 0.43 - 3.33).Conclusion. In this retrospective study, dual therapy with an oral third-generation cephalosporin and azithromycin was comparable to ceftriaxone-based regimens in the treatment of pharyngeal gonorrhea. Combination oral therapy with doxycycline was associated with an elevated risk of persistent or recurrent infection.

Concepts: Regression analysis, Oral sex, Sexually transmitted disease, Human sexual behavior, Chlamydia infection, Cephalosporin, Gonorrhea, Ceftriaxone

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Ceftolozane is a new cephalosporin with potent activity against Pseudomonas aeruginosa and Enterobacteriaceae. The neutropenic murine thigh-infection was used to determine which pharmacokinetic/pharmacodynamic index and magnitude drives efficacy of ceftolozane with gram-negative bacilli, compare the rate of in-vivo killing of ceftolozane with ceftazidime against P. aeruginosa, and determine the impact of different ratios of ceftolozane plus tazobactam on Enterobacteriaceae containing extended-spectrum-β-lactamases (ESBLs). Neutropenic mice had 10(6.2-7.1) cfu/thigh when treated with ceftolozane for 24 h with [1] varying doses (3.12 to 1600 mg/kg) and dosage intervals (3, 6, 12 and 24 h) against 2 Enterobacteriaceae, [2] 0.39-800 mg/kg every 6 h for 4 Enterobacteriaceae and 4 P. aeruginosa, and [3] 400 or 800 mg/kg with 2:1. 4:1, and 8:1 ratios of tazobactam against 5 Enterobacteriaceae with ESBLs. Pharmacokinetics of ceftolozane at 25, 100, and 400 mg/kg was linear with peak/dose values of 1.0-1.4 and half-lives of 12-14 min. T>MIC was the primary index driving efficacy. For stasis (1 log kill), T>MIC was 26.3% ± 2.1 (31.6% ± 1.6) for wild-type Enterobacteriaceae, 31.1% ± 4.9 (34.8% ±4.4) for Enterobacteriaceae with ESBLs, and 24.0% ± 3.3 (31.5% ± 3.9) for P. aeruginosa. At 200 mg/kg every 3 h, the rate of in-vivo killing of P. aeruginosa was faster with ceftolozane than with ceftazidime (-0.34 to -0.41 versus -0.21 to -0.24 log(10) cfu/thigh/h). The 2:1 ratio of ceftolozane with tazobactam was the most potent combination studied. T>MIC required for ceftolozane is less than with other cephalosporins and may be due to more rapid killing.

Concepts: Escherichia coli, Pseudomonas aeruginosa, Pseudomonas, Gram negative bacteria, Beta-lactamase, Pseudomonadales, Cephalosporin, Ceftazidime

28

An increased incidence and severity of invasive group A streptococcus (GAS) infections over the past decade have been reported by several authors, but GAS remains an uncommon cause of bacterial meningitis. The aim of this study was to describe and analyze the clinical and biological data of GAS meningitis by reporting 10 new cases of pediatric GAS meningitis and making a literature review. The mean age of patients, seven girls and three boys, was 3 years. There was a history of preexisting or concomitant community-acquired infection in five patients over 10. The outcome was fatal in two cases. All patients received an initial empirical antimicrobial therapy with a third generation cephalosporin switched in six cases to amoxicillin. The prognosis for this type of streptococcal meningitis is usually good, but death may occur even in children without any identified risk factor for severe infection.

Concepts: Inflammation, Bacteria, Streptococcus pneumoniae, Streptococcus pyogenes, Streptococcus, Penicillin, Group A streptococcal infection, Cephalosporin

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Photodegradation may be the most important elimination process for cephalosporin antibiotics in surface water. Cefazolin (CFZ) and cephapirin (CFP) underwent mainly direct photolysis (t(½) = 0.7, 3.9 h), while cephalexin (CFX) and cephradine (CFD) were mainly transformed by indirect photolysis, which during the process a bicarbonate-enhanced nitrate system contributed most to the loss rate of CFX, CFD, and cefotaxime (CTX) (t(½) = 4.5, 5.3, and 1.3 h, respectively). Laboratory data suggested that bicarbonate enhanced the phototransformation of CFD and CFX in natural water environments. When used together, NO(3)(-), HCO(3)(-), and DOM closely simulated the photolysis behavior in the Jingmei River and were the strongest determinants in the fate of cephalosporins. TOC and byproducts were investigated and identified. Direct photolysis led to decarboxylation of CFD, CFX, and CFP. Transformation only (no mineralization) of all cephalosporins was observed through direct photolysis; byproducts were found to be even less photolabile and more toxic (via the Microtox test). CFZ exhibited the strongest acute toxicity after just a few hours, which may be largely attributed to its 5-methyl-1,3,4-thiadiazole-2-thiol moiety. Many pharmaceuticals were previously known to undergo direct sunlight photolysis and transformation in surface waters; however, the synergistic increase in toxicity caused by this cocktail (via pharmaceutical photobyproducts) cannot be ignored and warrants future research attention.

Concepts: Medicine, Water, Toxicology, Beta-lactam antibiotic, Cephalosporin, Surface water, Cephalosporin antibiotics, Cefalotin

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An appropriate antibiotherapy is crucial for the safety and recovery of patients. Depending on the clinical conditions of patients, the required dose to effectively eradicate an infection may vary. An inadequate dosing not only reduces the efficacy of the antibiotic, but also promotes the emergence of antimicrobial resistances. Therefore, a personalized therapy is of great interest for improved patients' outcome and will reduce in long-term the prevalence of multidrug-resistances. In this context, on-site monitoring of the antibiotic blood concentration is fundamental to facilitate an individual adjustment of the antibiotherapy. Herein, we present a bioinspired approach for the bedside monitoring of free accessible ß-lactam antibiotics, including penicillins (piperacillin) and cephalosporins (cefuroxime and cefazolin) in untreated plasma samples. The introduced system combines a disposable microfluidic chip with a naturally occurring penicillin-binding protein, resulting in a high-performance platform, capable of gauging very low antibiotic concentrations (less than 6 ng ml(-1)) from only 1 µl of serum. The system’s applicability to a personalized antibiotherapy was successfully demonstrated by monitoring the pharmacokinetics of patients, treated with ß-lactam antibiotics, undergoing surgery.

Concepts: Medicine, Bacteria, Virus, Antibiotic resistance, Antibiotic, Penicillin, Beta-lactam antibiotic, Cephalosporin

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To evaluate the association between income status of a country and antimicrobial resistance (AMR) prevalence in the three most common bacteria causing infections in hospitals and in the community (third generation cephalosporin [3GC] resistant Escherichia coli, methicillin resistant Staphylococcus aureus [MRSA], and 3GC resistant Klebsiella species).

Concepts: Bacteria, Pneumonia, Staphylococcus aureus, Antibiotic resistance, Escherichia coli, Methicillin-resistant Staphylococcus aureus, Penicillin, Cephalosporin

9

The emergence and spread of carbapenem-resistant Gram-negative pathogens is a global public health problem. The acquisition of metallo-β-lactamases (MBLs) such as NDM-1 is a principle contributor to the emergence of carbapenem-resistant Gram-negative pathogens that threatens the use of penicillin, cephalosporin and carbapenem antibiotics to treat infections. To date, a clinical inhibitor of MBLs that could reverse resistance and re-sensitize resistant Gram-negative pathogens to carbapenems has not been found. Here we have identified a fungal natural product, aspergillomarasmine A (AMA), that is a rapid and potent inhibitor of the NDM-1 enzyme and another clinically relevant MBL, VIM-2. AMA also fully restored the activity of meropenem against Enterobacteriaceae, Acinetobacter spp. and Pseudomonas spp. possessing either VIM or NDM-type alleles. In mice infected with NDM-1-expressing Klebsiella pneumoniae, AMA efficiently restored meropenem activity, demonstrating that a combination of AMA and a carbapenem antibiotic has therapeutic potential to address the clinical challenge of MBL-positive carbapenem-resistant Gram-negative pathogens.

Concepts: Medicine, Bacteria, Antibiotic resistance, Penicillin, Beta-lactam antibiotic, Beta-lactamase, Cephalosporin, Carbapenem

9

The U.S. Food and Drug Administration recently issued new rules for using ceftiofur in food animals in part because of an increasing prevalence of enteric bacteria that are resistant to 3(rd)-generation cephalosporins. Parenteral ceftiofur treatment, however, has limited effects on enteric bacteria so we tested the hypothesis that excreted ceftiofur metabolites exert significant selection pressure for ceftiofur-resistant Escherichia coli in soil. Test matrices were prepared by mixing soil with bovine feces and adding urine containing ceftiofur metabolites (CFM) (0 ppm, ∼50 ppm and ∼100 ppm). Matrices were incubated at 23°C or 4°C for variable periods of time after which residual CFM was quantified using a bioassay. Bla(CMY-2) plasmid-bearing ceftiofur resistant (cef®) E. coli and one-month old calves were used to study the selection effects of CFM and transmission of cef® bacteria from the environment back to animals. Our studies showed that urinary CFM (∼13 ppm final concentration) is biologically degraded in soil within 2.7 days at 23°C, but persists up to 23.3 days at 4°C. Even short-term persistence in soil provides a >1 log(10) advantage to resistant E. coli populations, resulting in significantly prolonged persistence of these bacteria in the soil (∼two months). We further show that resistant strains readily colonize calves by contact with contaminated bedding and without antibiotic selection pressure. Ceftiofur metabolites in urine amplify resistant E. coli populations and, if applicable to field conditions, this effect is far more compelling than reported selection in vivo after parenteral administration of ceftiofur. Because ceftiofur degradation is temperature dependent, these compounds may accumulate during colder months and this could further enhance selection as seasonal temperatures increase. If cost-effective engineered solutions can be developed to limit ex vivo selection, this may limit proliferation for ceftiofur resistant enteric bacteria while preserving the ability to use this important antibiotic in food animal production.

Concepts: Bacteria, Gut flora, Antibiotic resistance, Escherichia coli, Enterobacteriaceae, Escherichia, Proteobacteria, Cephalosporin

8

Although cephalosporins are the cornerstone of treatment of Neisseria gonorrhoeae infections, cefixime is the only oral antimicrobial option. Increased minimum inhibitory concentrations (MICs) to cefixime have been identified worldwide and have been associated with reports of clinical failure.

Concepts: Neisseria gonorrhoeae, Cephalosporin, Neisseria, Gonorrhea