Fourth-generation Agents Research Articles

Crime Scene Novichok—Optical Detection of Fourth-Generation Agents (FGAs) Using Handheld Forensic Light Sources

Novichok-like or fourth-generation agents (FGAs) are chemical warfare agents (CWAs) which have been gaining attention since their use in assassination attempts on Sergei Skripal and Alexei Navalny. Due to their physicochemical properties, these substances are difficult to detect by implemented technologies, resulting in massive response efforts if their occurrence is suspected in a civilian environment. In this work, an approach is presented that uses handheld forensic light sources to visually detect surfaces contaminated with Novichok. More than 100 different wavelength combinations were applied to seven substances chosen to represent the newly listed schedule 1 subgroups in the Annex on Chemicals of the Chemical Weapons Convention. One waveband was identified as promising, which allowed the optical detection of all tested substances. Several surfaces, which could be affected in case of a possible attack using novichok-like nerve agents, were also successfully evaluated. The proposed procedure could be implemented for CBRN responders and security agencies to significantly reduce response efforts, thereby diminishing the overall threat posed by this group of chemicals (FGAs). This procedure was also extended to carbamates and CWAs.

Antimicrobial resistance of mineral water in Pseudomonas aeruginosa

Mineral water is a product that deserves attention for recognition of their quality, however mineral waters are not sterile and microorganisms present of its own , indigenous , existing prior to any treatment or processing. Bacteria of the genera Pseudomonas, Acinetobacter, Alcaligenes, Flavobacterium, Micrococus, and Bacillus are considered. These microorganisms, particularly the genus Pseudomonas , after industrial bottling process multiply rapidly , causing changes in the quality mineral water and triggering gastrointestinal disorders. The treatment against P. aeruginosa requires the combination of several classes of antibiotics, including beta- lactams third and fourth generation agents , aminoglycosides , and quinolones carbepenemas , among others . Because bacteria are able to develop resistance to antibiotics through various mechanisms, such as modification of the permeability system, production of beta - lactamases , transfer of R factors by conjugation or overexpression of efflux.

Review of third-and fourth-generation fluoroquinolones in ophthalmology: in-vitro and in-vivo efficacy

Beginning with second-generation ciprofloxacin 0.3% and ofloxacin 0.3%, fluoroquinolones have been widely used in the treatment and prophylaxis of ocular infections. However, their in-vitro potencies have been decreasing steadily since their introduction. Third-generation levofloxacin 0.5% produces higher ocular tissue penetration, thereby reducing the risk of selecting for decreased fluoroquinolone potency. Fourth-generation gatifloxacin 0.3% and moxifloxacin 0.5% have structural modifications that both reduce risk of resistance and improve potency against Gram-positive bacteria. A new third-generation formulation, levofloxacin 1.5%, was recently introduced, demonstrating increased ocular penetration compared with gatifloxacin 0.3% but clinical equivalence to its second-generation parent, ofloxacin 0.3%, in two randomized trials. We investigated the therapeutic potential of levofloxacin 1.5% and compared it to that of existing fourth-generation fluoroquinolones. A MEDLINE search was conducted using the following search terms: moxifloxacin or gatifloxacin; levofloxacin; minimum inhibitory concentration or prevention or prophylaxis; keratitis or endophthalmitis. Nine eligible studies published between 2002 and 2008 were identified, eight of which are presented. The five in-vitro studies demonstrated that moxifloxacin and gatifloxacin are statistically more potent than levofloxacin against Gram-positive organisms and similar in potency in most cases of Gram-negative bacteria. In-vivo animal models testing moxifloxacin or gatifloxacin against levofloxacin 0.5% (no clinical trials testing the efficacy of levofloxacin 1.5% have yet been published) demonstrated that fourth-generation agents were superior to third-generation levofloxacin 0.5% for prophylaxis of Gram-positive bacteria-induced infections and were equal to, or better than, levofloxacin 0.5% for the treatment of Gram-negative infections. Fourth-generation agents have increased potency against Gram-positive bacteria compared with levofloxacin, while maintaining similar potency against Gram-negative bacteria. Although levofloxacin 1.5% has demonstrated superior ocular penetration relative to gatifloxacin, the limited available data do not suggest this translates into superior clinical activity compared with moxifloxacin, which has significantly greater ocular penetration and better Gram-positive potency than gatifloxacin.

Fluoroquinolones compared to 1% azithromycin in DuraSite® for bacterial conjunctivitis [from Lichenstein and Granet] and Response to correspondence [from Friedlaender and Protzko] ||FREE PAPER||

Fluoroquinolones compared to 1% azithromycin in DuraSite® for bacterial conjunctivitis [from Lichenstein and Granet] and Response to correspondence [from Friedlaender and Protzko] ||FREE PAPER||

De la première à la quatrième génération de dihydropyridines : vers une meilleure efficacité et une meilleure tolérance

Dihydropyridines are among the most widely used drugs for the management of cardiovascular disease. Introduced in the 1960s, dihydropyridines have undergone several changes to optimise their efficacy and safety. Four generations of dihydropyridines are now available. The first-generation (nicardipine) agents have proven efficacy against hypertension. However, because of their short duration and rapid onset of vasodilator action, these drugs were more likely to be associated with adverse effects. The pharmaceutical industry responded to this problem by designing slow-release preparations of the short-acting drugs. These new preparations (second generation) allowed better control of the therapeutic effect and a reduction in some adverse effects. Pharmacodynamic innovation with regard to the dihydropyridines began with the third-generation agents (amlodipine, nitrendipine). These drugs exhibit more stable pharmacokinetics, are less cardioselective and, consequently, well tolerated in patients with heart failure. Highly lipophilic dihydropyridines are now available (lercanidipine, lacidipine). These fourth-generation agents provide a real degree of therapeutic comfort in terms of stable activity, a reduction in adverse effects and a broad therapeutic spectrum, especially in myocardial ischaemia and potentially in congestive heart failure.

Antimicrobial susceptibility of major pathogens of orofacial odontogenic infections to 11 beta-lactam antibiotics.

In this study, we evaluated the current effectiveness of 11 beta-lactam antibiotics for treatment of orofacial odontogenic infections by determining the antimicrobial susceptibility of the major pathogens. The antimicrobial susceptibilities of viridans streptococci (n = 47), Peptostreptococcus (n = 67), Porphyromonas (n = 18), Fusobacterium (n = 57), black-pigmented Prevotella (n = 59) and non-pigmented Prevotella (n = 47) isolated from pus specimens of 93 orofacial odontogenic infections to penicillin G, cefmetazole, flomoxef, cefoperazone, cefoperazone/sulbactam, ceftazidime, cefpirome, cefepime, cefoselis, imipenem and faropenem were determined using the agar dilution method. Penicillin G, most cephalosporins, imipenem and faropenem worked well against viridans streptococci, Peptostreptococcus, Porphyromonas and Fusobacterium. Penicillin G and most cephalosporins, including fourth-generation agents, were not effective against beta-lactamase-positive Prevotella, though they were effective against beta-lactamase-negative strains. Cefmetazole, cefoperazone/sulbactam, imipenem and faropenem expressed powerful antimicrobial activity against beta-lactamase-positive Prevotella. In conclusion, penicillins have the potential to be first-line agents in the treatment of orofacial odontogenic infections. Most of the other beta-lactam antibiotics, including fourth-generation cephalosporins, were not found to have greater effectiveness than penicillins. In contrast, cefmetazole, cefoperazone/sulbactam, imipenem and faropenem were found to have greater effectiveness than penicillins.

Detection of β-lactamase-mediated resistance

beta-Lactams are the most widely used antibiotics, and beta-lactamases are the greatest source of resistance to them. An understanding of beta-lactamase detection and identification is therefore valuable. Colorimetric, acidimetric and iodometric tests of beta-lactamase production are good, rapid indicators of penicillin and ampicillin resistance in Haemophilus, Moraxella and Neisseria spp. These methods can also be applied to Gram-negative aerobic bacilli but are less useful, since the usual question is not whether a beta-lactamase is produced by these organisms, but which beta-lactamase? Accurate identification of the beta-lactamases of Enterobacteriaceae demands gene or protein sequencing, but the broad type of enzyme produced by an isolate can often be inferred from antibiotic susceptibility data. Resistance to ceftazidime or cefpodoxime implies extended-spectrum beta-lactamase (ESBL) production in Escherichia coli and Klebsiella spp., especially if susceptibility to cefoxitin is retained. ESBL production can be confirmed with double disc tests or with various commercial kits. Derepression of AmpC beta-lactamases in Enterobacter spp. and Citrobacter freundii is another important mechanism and can be inferred from cross-resistance to beta-lactamase inhibitor combinations and to all cephalosporins except fourth-generation agents. Antagonism between cefoxitin and cefotaxime can be used to infer the presence of inducible AmpC enzymes in these species, indicating the risk of segregation of derepressed mutants, but in general this risk is better predicted from accurate speciation.

The Cephalosporins

The cephalosporins are a large group of related beta-lactam antimicrobial agents. Favorable attributes of the cephalosporins include low rates of toxicity, relatively broad spectrum of activity, and ease of administration. Various cephalosporins are effective for treatment of many conditions, including pneumonia, skin and soft tissue infections, bacteremia, and meningitis. Differences among the numerous cephalosporin antimicrobial agents are sometimes subtle; however, an understanding of these differences is essential for optimal use of these agents. As a result of widespread use of cephalosporins, bacterial resistance to these drugs is increasingly common. New, fourth-generation agents (such as cefepime) offer an alternative for the treatment of infections caused by some drug-resistant microorganisms.

Cephalosporins: an update.

The cephalosporins are the largest and most diverse family of antimicrobial agents available. Although they rarely are considered drugs of first choice for the therapy of bacterial infections, they are the most commonly prescribed agents for both ambulatory and hospitalized patients. The first-generation agents have the most limited spectrum of bactericidal activity, but they are the most potent against Gram-positive microbes. The third- and fourth-generation agents have a broad spectrum of activity that includes the majority of Gram-negative pathogens. However, they are less active than their first-generation counterparts against Gram-positive bacteria, especially S aureus. The cephalosporins generally are well tolerated, and the oral agents are palatable. However, their use is limited by increasing resistance among certain groups of bacteria and high cost, especially of the parenteral and recently licensed oral agents. The prudent physician need not be familiar with all cephalosporins, but should be knowledgeable about a select few.

A new therapeutic option for the treatment of pneumonia

Patients with bacterial pneumonia often are treated empirically with parenteral broad-spectrum antimicrobials intended to cover potential gram-negative and gram-positive pathogens. However, beta-lactamase-mediated resistance has developed to many of these antimicrobials, particularly third-generation cephalosporins, and has led to the development of fourth-generation agents that are relatively beta-lactamase stable. The purpose of these studies was to compare the efficacy and safety of the fourth-generation agent, cefepime, with that of the third-generation agent, ceftazidime, in the treatment of hospitalized patients with moderate-to-severe bacterial pneumonia. A total of 336 (97 evaluable) patients were enrolled in an open-label study, and 99 (23 evaluable) patients were enrolled in a blinded study of patients with lower respiratory tract infections (LRTI) including pneumonia. Patients were randomized to receive either cefepime 1 g every 12 hours or ceftazidime 1 g every 8 hours given as an intravenous infusion over 30 minutes. Efficacy analysis included the evaluable patients while the safety analysis included all patients. The results in the open-label study were as follows: In patients with pneumonia, clinical response was satisfactory in 58 (85%) of 68 patients in the cefepime group and 21 (72%) of 29 patients in the ceftazidime group. Bacteriologic eradication occurred for 75 (93%) of 81 pathogens and 30 (94%) of 32 pathogens isolated from the 68 cefepime-treated patients and 29 ceftazidime-treated patients, respectively. The results in the blinded study were as follows: In patients with pneumonia, clinical response was satisfactory in 12 (80%) of 15 cefepime patients and in 7 (88%) of 8 ceftazidime patients, and the bacteriologic eradication rates were 85% (17/20 pathogens) and 73% (8/11 pathogens) isolated from the 15 cefepime-treated patients and the eight ceftazidime-treated patients, respectively. Among the most frequent adverse events in both groups were nausea, diarrhea, vomiting, and abdominal pain. Similar adverse events were noted in the 99 patients in the blinded study. These studies indicate that the efficacy and safety of cefepime administered at 1 g twice daily is comparable to that of ceftazidime administered at 1 g three times daily for treatment of hospitalized patients with pneumonia caused by susceptible pathogens.