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Contribution of animal models in the search for effective therapy for endocarditis due to enterococci with high-level resistance to gentamicin.

Earlier studies suggest that ampicillin and amoxicillin are more effective than other beta-lactam agents in killing enterococci, although beta-lactam agents are slowly and incompletely bactericidal against most strains of Enterococcus faecalis. We previously showed that continuous infusion of ampicillin is more effective than intermittent administration in decreasing the number of enterococci in valvular vegetations of rats with catheter-induced endocarditis that are treated for 5 days. In this model, we found ampicillin plus sulbactam more effective than ampicillin alone against a beta-lactamase-producing enterococcal strain with high-level resistance to gentamicin. Daptomycin therapy produced results approximately equal to those of ampicillin plus sulbactam. Vancomycin and teicoplanin given for 5 days at doses producing equivalent serum levels had approximately equal efficacy. However, 10-day therapy with low-dose teicoplanin was considerably more effective than similar treatment with vancomycin. High-dose teicoplanin for 5 days produced sterile valves in 82% of the animals studied.

Ampicillin↗

Comparative in-vitro activity of four peptide antibiotics against penicillin-resistant Streptococcus pneumoniae isolated from cerebrospinal fluid (CSF).

The in-vitro activity of four peptide antibiotics against 43 penicillin-resistant Streptococcus pneumoniae isolated from cerebrospinal fluid (CSF) was evaluated. The activity of SKF104662 was slightly greater to that of vancomycin, teicoplanin and daptomycin (MICs for 90% of the isolates tested 0.06, 0.25, 0.12 and 0.25 mg/L, respectively) and superior to the other 15 drugs tested. The serotype of these penicillin-resistant strains was also determined. The strains that belonged to the predominant serotype 9 were resistant only to penicillin. All six erythromycin- and clindamycin-resistant strains belonged to serotype 6 and three of them were also resistant to chloramphenicol and tetracycline (plus penicillin).

Anti-Bacterial Agents↗

Autolysis of methicillin-resistant and -susceptible Staphylococcus aureus.

The autolytic activities, including unstimulated, Triton X-100-stimulated, and daptomycin-induced, of various sets of methicillin-resistant and related methicillin-susceptible strains were compared. Faster rates of autolysis were noted in two heterogeneous methicillin-resistant transductants than in their methicillin-susceptible parental recipients, in a heterogeneous resistant strain than in a susceptible derivative created by chemical mutagenesis, and in a homogeneous resistant strain than in a derivative that had decreased methicillin resistance and was created by transposon Tn551 mutagenesis. These results suggest that the presence of the methicillin resistance region, mec, either directly or indirectly through an interaction with other host genes, confers a faster rate of autolysis on strains. Various auxilliary genes are known to affect methicillin resistance expression, and one of these genes, femA, was necessary for the expression of this faster rate of autolysis. These differences in autolytic activities were not observed in isolated crude cell walls retaining autolytic activities, suggesting different modes of regulation of autolysins in intact cells and isolated walls. In contrast, one homogeneous, highly resistant strain, DU4916, had a lower autolytic activity than did derived heterogeneous resistant and susceptible strains created by chemical mutagenesis and a strain that had decreased resistance and was created by transposon mutagenesis. Our observations suggest that methicillin resistance expression is associated with an enhanced rate of autolysis, in heterogeneous resistant strains at least.

Autolysis↗

[Recent trend and development of novel antimicrobial agents for MRSA infections].

Gram-positive organisms such as Staphylococcus aureus (including MRSA), coagulase-negative staphylococci, Enterococcus spp., and Streptococcus spp. have in recent years emerged as significant pathogens in hospitals and are now being isolated more frequently than gram-negative bacilli. These organisms are often multidrug resistant. Therefore, alternative agents with potent activity against gram-positive organisms are of considerable interest. In addition to the glycopeptide antibiotic vancomycin and the aminoglycoside antibiotic arbekacin, which can be used in MRSA infections, teicoplanin, RP 59500 and daptomycin are now under basic research in Japan. These antimicrobial agents are very active against gram-positive organisms, including MRSA and appear to be potent agents against infections due to gram-positive cocci, particularly MRSA.

Daptomycin↗

[Bacteremia caused by vancomycin-resistant Enterococcus faecalis. Report of 2 cases].

The rising concern about nosocomial bacteremia due to vancomycin-resistant E. faecalis in Spanish hospitals. Retrospective review of the medical records of two patients with nosocomial bacteremia due to E. faecalis resistant to vancomycin. Both patients (a 78 years-old male and a 65 years-old female) were admitted in two separate hospital units. None of them had been previously treated with vancomycin, and both patients had severe underlying diseases. The two strains isolated showed high-level vancomycin and teicoplanin resistance, although they were sensitive to daptomycin. No other strain with high level glycopeptide antibiotic resistance was isolated in the hospital during the following 23 months. This occasional resistance to glycopeptides among enterococci has been shown also in other Spanish hospitals. The increasing incidence of penicillin and aminoglycoside resistance among enterococci in our environment could have a practical impact, either for the clinical laboratory and/or for therapeutic decisions in patients with infections due to this microorganism.

Aged↗

What's new in clinical pharmacology and therapeutics.

The US Food and Drug Administration (FDA) has approved several new drugs in the last few years. We have summarized a few of these that should be of interest to a primary care physician. These belong to either a new class of drugs or have a better drug profile in terms of ease of administration, prolonged duration of action, or fewer side effects. Daptomycin is a cyclic lipopeptide, active against methycillin resistant Staphylococcus aureus (MRSA). Telithromycin is a ketolide that can be used in place of macrolide antibiotics. Rifaximin is a semi-synthetic derivative of rifampin approved by the FDA for treatment of traveller's diarrhea. Pramlintide is an injectable synthetic amylin useful in treating type 1 and 2 diabetes. Tiotropium is an anti-cholinergic bronchodilator that can be taken once a day for treatment of chronic obstructive pulmonary disease. Lanthanum Carbonate is useful in treatment of hyperphosphatemia in patients with end stage renal disease. Flumist is an intranasal influenza vaccine. Eszopiclone is a new hypnotic that has fewer side effects. Memantine is in a new class of drugs useful in the treatment of Alzheimer's disease. Ibandronate is a new bisphosphonate approved for once a month use for osteoporosis in postmenopausal women. Acamprosate is approved for treatment of alcohol dependence.

Acamprosate↗

The nonribosomal peptide biosynthetic system--on the origins of structural diversity of peptides, cyclopeptides and related compounds.

A variety of peptides have been detected in microorganisms. Some have found applications in various fields, for example the classical beta-lactam antibiotics, immunosuppressors like cyclosporin, promising new antibacterials like teichoplanin or daptomycin and antifungals like echinocandin. For none of these has it been established how their complicated biosynthetic pathways have evolved or what functions they fulfill within or for their producers. So it is unclear what selection processes limit the range of their structural analogues within various groups of microorganisms. We here consider recent data in the field of biosynthesis and how they may suggest mechanisms of genetic diversity. These may illustrate the complexity of genetic and intracellular organization of biosynthetic pathways and indicate the cellular context of some metabolites related to the complex background of the production of each metabolite. Research focusing on various targets like the increase of productivity of fermentations or the spread of resistances to antibacterials is slowly being understood.

Amino Acid Sequence↗

Isolation of vancomycin-resistant enterococci in haematologic patients.

After the occurrence of septicaemia with a vancomycin-resistant Enterococcus faecalis strain in a patient, it was decided to determine the number of carriers of vancomycin-resistant cocci among haematologic patients. During a period of six months 135 stool samples from 25 children, and 400 samples from 70 adults were studied. All samples from the children were negative for vancomycin-resistant cocci. Nine of the adult patients had cultures positive for cocci, all identified as enterococci, which were highly resistant to vancomycin (MIC greater than 250 micrograms/ml), sensitive to amoxicillin, moderately resistant to gentamicin, slightly resistant to teicoplanin, and sensitive to daptomycin. None of these patients had been given vancomycin prior to the isolation of the vancomycin-resistant enterococci.

Adult↗

Antibiotics for treatment of resistant gram-positive coccal infections.

Vancomycin is considered the workhorse for the treatment of most drug-resistant gram-positive bacterial infections. However, concerns have been raised regarding the increasing rates of vancomycin-resistant enterococci and the clinical shortcomings of vancomycin in the treatment of invasive Staphylococcus aureus infections. Resources have been committed to the development of antimicrobial agents with activity against these organisms. This review will focus on the newer antibacterial agents that have been developed for the treatment of resistant gram-positive pathogens. Included in this review are the agents: quinupristin-dalfopristin, linezolid, daptomycin, telithromycin, and tigecycline.

Anti-Bacterial Agents↗

[Antibiotic therapy: progress and development of resistance].

This contribution illustrates reasons, spread, and mechanisms of development of resistance especially in gram-positive microorganisms such as methicillin resistant staphylococcus aureus (MRSA) or vancomycin resistant enterokoccus (VRE). Possibilities of overcoming these are described as well as strategies for antibacterial therapy with recently developed antibiotics against multiple resistant microorganisms. These are linezolid as an oxazolidinone, daptomycin as a lipopeptid and tigecyclin as a new glycylcycline, which are already on the market or will be launched soon in Germany. Differences in magnitude and frequency of still existing resistances between hospital and practice are discussed with respect to their importance for the internal physician.

Anti-Bacterial Agents↗

Antimicrobial agents for treatment of serious infections caused by resistant Staphylococcus aureus and enterococci.

As clinicians increasingly contend with infections due to staphylococci or enterococci resistant to, or failing treatment with, traditional antimicrobial agents, understanding the potential roles of older as well as more recently introduced antimicrobial agents becomes important. Older agents, such as clindamycin and trimethoprim-sulfamethoxazole, have been used to treat infections due to community-acquired methicillin-resistant Staphylococcus aureus. Among the licensed agents, quinupristin-dalfopristin, linezolid, daptomycin, and tigecycline are active in vitro against most strains of methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus faecium, but these agents differ in their approved clinical indications. New agents currently under investigation may further expand treatment options.

Anti-Bacterial Agents↗

The lipopeptide antibiotic A54145 biosynthetic gene cluster from Streptomyces fradiae.

Ca(2+)-dependent cyclic lipodepsipeptides are an emerging class of antibiotics for the treatment of infections caused by Gram-positive pathogens. These compounds are synthesized by nonribosomal peptide synthetase (NRPS) complexes encoded by large gene clusters. The gene cluster encoding biosynthetic pathway enzymes for the Streptomyces fradiae A54145 NRP was cloned from a cosmid library and characterized. Four NRPS-encoding genes, responsible for subunits of the synthetase, as well as genes for accessory functions such as acylation, methylation and hydroxylation, were identified by sequence analysis in a 127 kb region of DNA that appears to be located subterminally in the bacterial chromosome. Deduced epimerase domain-encoding sequences within the NRPS genes indicated a D: -stereochemistry for Glu, Lys and Asn residues, as observed for positionally analogous residues in two related compounds, daptomycin, and the calcium-dependent antibiotic (CDA) produced by Streptomyces roseosporus and Streptomyces coelicolor, respectively. A comparison of the structure and the biosynthetic gene cluster of A54145 with those of the related peptides showed many similarities. This information may contribute to the design of experiments to address both fundamental and applied questions in lipopeptide biosynthesis, engineering and drug development.

Amino Acid Sequence↗

Agents for the Treatment of Multidrug-resistant Gram-positive Endocarditis.

Several newer agents with activity against multidrug- resistant gram-positive pathogens are available. These agents have in vitro and clinical data supporting their utility in the treatment of infections caused by pathogens such as methicillin-resistant staphylococci and vancomycin-resistant enterococci. Daptomycin appears to be rapidly bactericidal, and linezolid and quinupristin/dalfopristin also are cidal against staphylococci. Although the agents have several properties that are attractive for use in endocarditis, clinical data are limited. Further investigation with each agent and combination therapy are warranted before definitive recommendations can be made.

Journal Article↗

Vancomycin-Resistant Enterococcus: Infectious Endocarditis Treatment.

Vancomycin-resistant Enterococcus species represent serious gram-positive pathogens for which there is currently no recommended therapy. There are a number of new antibiotics with activity against these pathogens in development. Although there is a great deal of experience with some of these agents for skin and soft tissue infections, bacteremia, pneumonia, and intra-abdominal infections, there is currently little information available for the treatment of endocarditis. Animal and limited human data thus far suggest that new agents such as quinuprisitin-dalfopristin, LY333328 (a new glycopeptide antibiotic), and daptomycin (a lipopeptide antibiotic) may prove useful for this indication. Additional information, and especially combination treatment, are warranted to improve success and limit the emergence of resistance to these new antibiotics.

Journal Article↗

Effect of polyurethane catheters and bacterial biofilms on the in-vitro activity of antimicrobials against Staphylococcus epidermidis.

The effect of two polyurethane ['Cavafix Certo' (CAV); 'Viacath' (VIA)] catheters on the in-vitro activity of amikacin (AN), clindamycin (CM), cloxacillin (CX), ciprofloxacin (CIP), vancomycin (VA), teicoplanin (TEI) and daptomycin (DAP) against slime producing and non-producing Staphylococcus epidermidis strains was determined using a microdilution assay. None of the antimicrobial agents was significantly affected in the presence of the catheters. The susceptibility of S. epidermidis attached to CAV and VIA catheters was also evaluated. Minimum inhibitory concentration (MIC) values were similar when planktonic and attached bacteria were compared. Minimum bactericidal concentrations (MBCs) markedly increased in the presence of 6 and 48 h bacterial biofilms. These increases in MBC values occurred when either slime producing or non-producing strains were used, and in most cases were higher for CAV catheters than for VIA catheters. This phenomenon was shown not to be due to differences in bacterial adherence. It is concluded that the in-vitro bactericidal activity of certain antimicrobials markedly decreased when bacteria adhered to plastic catheters, but this effect could have been dependent partially on the nature of the catheters.

Anti-Bacterial Agents↗

Activity of cephalosporins against coagulase-negative staphylococci.

Staphylococcus epidermidis has become an increasingly important pathogen as the cause of serious postoperative infection after heart and orthopedic surgery. We studied the susceptibilities of 80 blood, sternotomy, and hip isolates to vancomycin, cefazolin, cefuroxime, oxacillin, erythromycin, ciprofloxacin, and ofloxacin. The MIC90 of methicillin-susceptible isolates was 4 micrograms/ml for cefazolin and cefamandole, 8 micrograms/ml for cefuroxime, and 4 micrograms/ml for vancomycin. At 48 hr the MIC90 rose to 32 micrograms/ml for cefazolin and greater than 128 micrograms/ml for cefuroxime, and remained at 4 micrograms/ml for cefamandole and vancomycin. The MIC90 of methicillin-resistant isolates at 48 hr was 16 micrograms/ml cefamandole, 64 micrograms/ml cefazolin, greater than 128 micrograms/ml cefuroxime, and 4 micrograms/ml vancomycin. Ciprofloxacin and ofloxacin inhibited the majority of isolates at 1 microgram/ml, and vancomycin at 4 micrograms/ml. The new peptolide, daptomycin, also inhibited S. epidermidis at less than or equal to 1 microgram/ml.

Cefamandole↗

Mechanisms of antimicrobial resistance in bacteria.

The treatment of bacterial infections is increasingly complicated by the ability of bacteria to develop resistance to antimicrobial agents. Antimicrobial agents are often categorized according to their principal mechanism of action. Mechanisms include interference with cell wall synthesis (eg, beta-lactams and glycopeptide agents), inhibition of protein synthesis (macrolides and tetracyclines), interference with nucleic acid synthesis (fluoroquinolones and rifampin), inhibition of a metabolic pathway (trimethoprim-sulfamethoxazole), and disruption of bacterial membrane structure (polymyxins and daptomycin). Bacteria may be intrinsically resistant to > or =1 class of antimicrobial agents, or may acquire resistance by de novo mutation or via the acquisition of resistance genes from other organisms. Acquired resistance genes may enable a bacterium to produce enzymes that destroy the antibacterial drug, to express efflux systems that prevent the drug from reaching its intracellular target, to modify the drug's target site, or to produce an alternative metabolic pathway that bypasses the action of the drug. Acquisition of new genetic material by antimicrobial-susceptible bacteria from resistant strains of bacteria may occur through conjugation, transformation, or transduction, with transposons often facilitating the incorporation of the multiple resistance genes into the host's genome or plasmids. Use of antibacterial agents creates selective pressure for the emergence of resistant strains. Herein 3 case histories-one involving Escherichia coli resistance to third-generation cephalosporins, another focusing on the emergence of vancomycin-resistant Staphylococcus aureus, and a third detailing multidrug resistance in Pseudomonas aeruginosa-are reviewed to illustrate the varied ways in which resistant bacteria develop.

Cephalosporin Resistance↗

Mechanisms of antimicrobial resistance in bacteria.

The treatment of bacterial infections is increasingly complicated by the ability of bacteria to develop resistance to antimicrobial agents. Antimicrobial agents are often categorized according to their principal mechanism of action. Mechanisms include interference with cell wall synthesis (e.g., beta-lactams and glycopeptide agents), inhibition of protein synthesis (macrolides and tetracyclines), interference with nucleic acid synthesis (fluoroquinolones and rifampin), inhibition of a metabolic pathway (trimethoprim-sulfamethoxazole), and disruption of bacterial membrane structure (polymyxins and daptomycin). Bacteria may be intrinsically resistant to > or =1 class of antimicrobial agents, or may acquire resistance by de novo mutation or via the acquisition of resistance genes from other organisms. Acquired resistance genes may enable a bacterium to produce enzymes that destroy the antibacterial drug, to express efflux systems that prevent the drug from reaching its intracellular target, to modify the drug's target site, or to produce an alternative metabolic pathway that bypasses the action of the drug. Acquisition of new genetic material by antimicrobial-susceptible bacteria from resistant strains of bacteria may occur through conjugation, transformation, or transduction, with transposons often facilitating the incorporation of the multiple resistance genes into the host's genome or plasmids. Use of antibacterial agents creates selective pressure for the emergence of resistant strains. Herein 3 case histories-one involving Escherichia coli resistance to third-generation cephalosporins, another focusing on the emergence of vancomycin-resistant Staphylococcus aureus, and a third detailing multidrug resistance in Pseudomonas aeruginosa--are reviewed to illustrate the varied ways in which resistant bacteria develop.

Adult↗