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Antimicrobial susceptibility of nisin resistant Listeria monocytogenes of dairy origin.

The antibiotic susceptibility of wild Listeria monocytogenes strains and their corresponding nisin resistant variants was assessed. The resistant strains were more sensitive to most of the tested antibiotics than their wild-type counterparts. A slight increase in MIC was observed for a few antibiotics including the membrane disturbing polymixin B. Cross-resistance was detected with two synthetic antimicrobial peptides. A lower C15/C17 ratio in the membrane fatty acid composition of the nisin resistant strains was found, and one strain pair showed a significant difference in surface hydrophobicity. As judged by these results, no clear correlation could be established between resistance to nisin and to worldwide-used antibiotics.

Anti-Bacterial Agents↗

Inhibition of alcohol dehydrogenase by bismuth.

Bismuth compounds have been widely used for the treatment of ulcers and Helicobacter pylori infection, and enzyme inhibition was thought to be crucial for bismuth anti-microbial activity. We have investigated the interaction of colloidal bismuth subcitrate (CBS) with alcohol dehydrogenase and our results demonstrate that bismuth can effectively inhibit the enzyme. Kinetic analysis revealed that CBS acted as a non-competitive inhibitor of yeast alcohol dehydrogenase. Both UV-vis and fluorescence data show that interaction of CBS with the enzyme exhibits biphasic processes. Bismuth can replace only half of Zn(II) from the enzyme (i.e., about one Zn(II) per monomer). Surprisingly, binding of CBS also induces the enzyme dissociation from its native form, tetramer into dimers. The inhibition of Bi(III) on the enzyme is probably due to its direct interference with the zinc sites. This study is likely to provide an insight into the mechanism of action of bismuth drugs.

Alcohol Dehydrogenase↗

Metagenomics--the key to the uncultured microbes.

It is widely accepted that up to 99.8% of the microbes present in many environments are not readily culturable. 'Metagenome technology' tries to overcome this bottleneck by developing and using culture-independent approaches. From the outset, metagenome-based approaches have led to the accumulation of an increasing number of DNA sequences, but until this time the sequences retrieved have been those of uncultured microbes. These genomic sequences are currently exploited for novel biotechnological and pharmaceutical applications and to increase our knowledge on microbial ecology and physiology of these microbes. Using the metagenome sequences to fully understand how complex microbial communities function and how microbes interact within these niches represents a major challenge for microbiologists today.

Bacteria↗

Using geographical information techniques to quantify the spatial structure of endolithic boring processes within sediment grains of marine stromatolites.

Marine stromatolites are generated through the interactions of environmental parameters and specific microbial processes. The activities of endolithic bacteria, that bore canals through calcium carbonate (CaCO(3)) sand grains (ooids) and reprecipitate the CaCO(3) as a single layer (i.e. micritic laminae) are especially important in the longer term stability of the stromatolite macrostructure. Image analysis and classification approaches have been used previously, but only seldom as a quantitative microscopic tool. Here, we develop a new approach that enables the quantification of microscale (i.e. micrometers to millimeters) spatial structure within marine stromatolites. To demonstrate our approach, images were acquired from two different layers of a stromatolite: "orange layers", where microboring of canals within ooids was relatively abundant, and "white layers" where microboring was greatly reduced or lacking. Images were then transformed into spatial maps. Computation of canal and ooid grain areas within each image was conducted and statistically compared between replicate samples from the two stromatolite layers. This allowed quantification of the areas of ooid grains that were microbored. Based on our results, we suggest that our method could be widely applicable to sedimentary environments, and other areas of fundamental research.

Bacteria↗

Changing patterns of resistance to new beta-lactam antibiotics. In vitro efficacy of cefoperazone against bacterial pathogens.

No evidence for significant increase in resistance to cefoperazone was detected in susceptibility test surveillance programs or in the literature through 1983, but rare endemic resistance to cefoperazone and some other newer beta-lactams was found. Medical centers contemplating the use of a third-generation drug for cost-containment should be aware of the susceptibility of isolates in their hospitals, and the drug's ability to withstand beta-lactamase hydrolysis by local pathogens. The possible dangers of inducible cephalosporins in certain Enterobacteriaceae and strains of Pseudomonas aeruginosa are discussed in the light of the physical and chemical characteristics of the newer antimicrobial agents. Criteria for judging the values of investigational beta-lactams are presented. These focus on the interaction of antimicrobial agents with host defense mechanisms and circulating blood elements.

Anti-Bacterial Agents↗

Antibiotic therapy for Pseudomonas aeruginosa bacteremia: outcome correlations in a prospective study of 200 patients.

PURPOSE AND PATIENTS AND METHODS: We performed a prospective clinical study of 200 consecutive patients with Pseudomonas aeruginosa bacteremias to analyze in vitro susceptibility and synergistic testing of antibiotics the patients received and clinical parameters to assess their relationship to survival. RESULTS: No significant correlation between in vitro susceptibility testing (minimal inhibitory concentrations/minimal bactericidal concentrations) and outcome could be demonstrated. Similarly, improved outcome could not be demonstrated for patients receiving antibiotic combinations that were synergistic in vitro (either time-kill or checker-board) versus those combinations that were not. There was also no correlation between results obtained by time-kill curve and checkerboard synergistic testing, i.e., combinations found to be synergistic by one method were not necessarily synergistic by the other method. Clinical parameters associated with improved survival were a urinary portal of entry and absence of neutropenia. Conversely, survival was significantly decreased when the portal was the respiratory tract. The mortality rate between patients receiving combination therapy (27%) and monotherapy (47%) was significant (p less than 0.02); this significant relationship held true for most subgroups including malignancy, nosocomial infection, and infection site. CONCLUSION: Increasing effort should be placed on ensuring timely administration of combination therapy to patients with P. aeruginosa bacteremia since the use of combination therapy was even more important in determining outcome than was underlying disease.

Adolescent↗

Effects of carbohydrate polymers applicable in saliva substitutes on the anti-Candida activity of a histatin-derived peptide.

The effects of polymers applicable in saliva substitutes on the anti-Candida activity of the cationic antimicrobial peptide dhvar1 were investigated. Dhvar1 is a derivative of the 14 C-terminal amino acids of histatin 5. The effects of the following polymers were tested: uncharged hydroxyethylcellulose (HEC), negatively charged xanthan (XG) and three types of negatively charged carboxymethylcellulose (CMC) of identical mass but different degrees of carboxylic acid-group substitution (DS). The effects were tested at pH 4.0, 7.0 and 8.5 in a killing assay. HEC had no effect at any pH tested; XG and the three types of CMC caused a decrease in activity at increasing concentrations. Within the CMC group, inhibition increased slightly with increasing DS. These results suggest that the reduction in activity associated with these polymers is the result of electrostatic interaction between the positively charged peptides and the negatively charged polymers. In the absence of polymers, no effect of pH was found on the activity of dhvar1. In the presence of the charged polymers XG and CMC, lowering the pH from 7.0 to 4.0 resulted in a decrease of dhvar1 activity. It was concluded that, with respect to the retention of activity, HEC is the most appropriate polymer for use in combination with dhvar1. However, for use in saliva substitutes XG seems more suitable because of its rheological properties. If XG or CMC are to be used, their reductive effect on the anti-Candida activity of dhvar1 should be compensated for by increasing the peptide dose.

Antifungal Agents↗

The fluoroquinolones.

The fluoroquinolone class of antibiotics promises to become as diverse and as important as beta-lactam agents. The fluoroquinolones inhibit bacterial DNA gyrase and are bactericidal. All fluoroquinolones have potent activity against most gram-negative bacteria; ciprofloxacin is the most active against Pseudomonas aeruginosa. Activity against gram-positive organisms is variable; methicillin-resistant Staphylococcus aureus has acquired resistance to the fluoroquinolones at an alarming rate. Currently available quinolones do not have, but new quinolone agents likely will have, substantial activity against anaerobic bacteria. Some quinolones are also active against Mycobacterium, Chlamydia, and Mycoplasma organisms. All fluoroquinolones have excellent absorption after oral administration; however, this process can be impaired by the presence of aluminum- or magnesium-containing antacids and by zinc, iron, or calcium supplements. Ciprofloxacin is also available for intravenous use. Although most fluoroquinolones do not achieve adequate cerebrospinal fluid levels, penetration into other tissues is excellent. Dosage adjustments for renal and hepatic dysfunction vary among the quinolones. Although side effects are rare, concomitant use of caffeine or theophylline with some quinolones may cause toxicity to the central nervous system. Because they may affect the development of cartilage, all fluoroquinolones are contraindicated in children, adolescents, and pregnant or breast-feeding women.

4-Quinolones↗

Antibiotic failure.

There are many possible causes of antibiotic drug failure, but the most common are drug fevers, untreatable infectious diseases, noninfectious diseases, or problems with incorrect or inadequate spectrum. Failure to respond to antibiotics includes the emergence of resistant organisms, superinfections, and drug interactions. The most common mistake made with apparent antibiotic failure is to change or add additional antibiotics. The most important strategy is to analyze the cause of the antibiotic failure by careful evaluation and use of appropriate diagnostic tests to avoid needless, expensive, and potentially dangerous antimicrobial therapy.

Anti-Bacterial Agents↗

Clindamycin.

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Bacteria↗

Emergence of trimethoprim-resistant enterobacteria in patients receiving long-term co-trimoxazole for the control of intractable urinary-tract infection.

In patients with previously intractable urinary-tract infection treated with low-dose co-trimoxazole for 6--58 (mean 32.7) months, the percentage of infected urines fell from 41.4 before treatment to 6.3 during treatment. Only 6 episodes of infection were due to trimethoprim-resistant bacteria. Results in a small group of patients in whom treatment was continued with trimethoprim alone were similar. Under the conditions of this study, long-term control of urinary-tract infection was not materially compromised by breakthrough infections due to trimethoprim-resistant organisms.

Bacteriuria↗

Expanded activity and utility of the new fluoroquinolones: a review.

In general, the fluoroquinolones developed over the past few years have greater potency, a broader spectrum of antimicrobial activity, greater in vitro efficacy against resistant organisms, and a better safety profile than other antimicrobial agents, including the older quinolones. The present review focuses on 4 new quinolones that are commercially available (levofloxacin, trovafloxacin, grepafloxacin, and sparfloxacin) and 3 that are currently undergoing clinical trials (gatifloxacin, moxifloxacin, and clinafloxacin). Examination of the minimum inhibitory concentrations of these drugs against gram-positive, gram-negative, anaerobic, and atypical organisms demonstrates their increased potency in vitro. The available clinical evidence, although sparse, suggests the potential enhanced efficacy of these drugs in the treatment of various community-acquired and nosocomial infections (eg, respiratory, urinary tract, and skin infections and sexually transmitted diseases). Compared with ciprofloxacin, their pharmacokinetic profiles demonstrate equivalent or greater bioavailability, higher plasma concentrations, and increased tissue penetration, as reflected in greater volume of distribution. Adverse events seen with most quinolones are mild. Serious adverse effects that may occur are phototoxicity (particularly with sparfloxacin) and prolongation of the QTc interval (seen with sparfloxacin and grepafloxacin). Drug interactions are possible between multivalent cation-containing compounds and all quinolones and between theophylline and both ciprofloxacin and grepafloxacin. Drugs that prolong the QTc interval should not be coadministered with sparfloxacin and grepafloxacin. Step-down therapy, a therapeutic and cost-saving advantage possible with gatifloxacin, levofloxacin, and moxifloxacin, allows the switching of patients from intravenous to oral therapy without having to change the dosage regimen or class of antibiotics. In addition to shortening the hospital stay and reducing the risk of venous complications, step-down therapy has been shown to cut hospital drug costs by 40% and hospitalization costs by 20%.

Animals↗

Caspofungin: an echinocandin antifungal agent.

BACKGROUND: The mainstays of treatment for nosocomial fungal infections have been amphotericin B and azole derivatives. Caspofungin acetate is a new echinocandin antifungal agent with a mechanism of action that targets a structural component of the fungal cell wall. OBJECTIVE: This article describes the pharmacologic properties and potential clinical usefulness of caspofungin. METHODS: Relevant information was identified through searches of MEDLINE (1966-September 2001). Iowa Drug Information Service (1966-September 2001), and International Pharmaceutical Abstracts (1970-September 2001), as well as meeting abstracts of the Infectious Diseases Society of America and the Interscience Conference on Antimicrobial Agents and Chemotherapy (1996-2001), using the terms caspofungin, MK-0991, pneumocandin, echinocandin, candin, and beta-(1,3)-glucan inhibitor. RESULTS: In vitro, caspofungin exhibits antifungal activity against an array of clinically important yeasts and molds, including Candida and Aspergillus spp. The proposed susceptibility breakpoint for caspofungin against Candida spp, the most common cause of nosocomial fungal infections, is a minimum inhibitory concentration of < or =1 microg/mL. In humans, caspofungin has a volume of distribution of 9.67 L, is extensively bound to albumin (97%), has a plasma elimination half-life of 9 to 11 hours, and is metabolized to inactive metabolites in the liver. Dose adjustment based on age, sex, race, or renal function does not appear to be necessary, although patients with moderate hepatic insufficiency (Child-Pugh score 7-9) should receive a lower maintenance dose. The results of clinical trials, although somewhat preliminary, suggest that caspofungin is effective in the treatment of esophageal and oropharyngeal candidiasis and invasive aspergillosis. When combined with other antifungal agents, caspofungin produces a synergistic or additive effect against a variety of clinically important fungi. The most commonly reported adverse events with caspofungin have included fever, infusion-related reactions, headache, nausea, elevations in liver transaminase levels, and histamine-type reactions. The recommended dosage in adults is 70 mg IV on day 1 followed by 50 mg/d, with the duration of treatment depending on the severity of the patient's underlying condition and the clinical response. CONCLUSION: Although additional studies are needed, caspofungin appears to be a promising agent for the treatment of patients with difficult-to-treat or life-threatening fungal infections.

Aged↗

Erythromycin, clarithromycin, and azithromycin: are the differences real?

Erythromycin, clarithromycin, and azithromycin are clinically effective for the treatment of common respiratory and skin/skin-structure infections. Erythromycin and azithromycin are also effective for treatment of nongonococcal urethritis and cervicitis due to Chlamydia trachomatis. Compared with erythromycin, clarithromycin and azithromycin offer improved tolerability. Clarithromycin, however, is more similar to erythromycin in pharmacokinetic measures such as half-life, tissue distribution, and drug interactions. Misunderstandings about differences among the macrolides (erythromycin and clarithromycin) and the azalide (azithromycin) in terms of pharmacokinetics and pharmacodynamics, spectrum of activity, safety, and cost are common. The uptake and release of these compounds by white blood cells and fibroblasts account for differences in tissue half-life, volume of distribution, intracellular:extracellular ratio, and in vivo potency. Although microbiologic studies reveal that gram-positive pathogens are equally susceptible to these agents, significantly more isolates of Haemophilus influenzae are susceptible to azithromycin than to erythromycin or clarithromycin. Concentrations achieved at the infection site and duration above the minimum inhibitory concentration are as important as in vitro activity in determining in vivo activity against bacterial pathogens. Analysis of safety data indicates differences among these agents in drug interactions and use in pregnancy. Analysis of safety data reveals pharmacokinetic drug interactions for erythromycin and clarithromycin with theophylline, terfenadine, and carbamazepine that are not found with azithromycin. Both erythromycin and azithromycin are pregnancy category B drugs; clarithromycin is a category C drug. The numerous differences in pharmacokinetics, microbiology, safety, and costs among erythromycin, clarithromycin, and azithromycin can be used in the judicious selection of treatment for indicated infections.

Anti-Bacterial Agents↗