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PubMed1994

Use of multivariate analysis to compare antimicrobial agents on the basis of in vitro activity data.

Multivariate techniques such as principal component analysis or similar factor analysis help in analyses of the simultaneous interrelationships among several variables. A comparative multivariate analysis on the in vitro activities of eight antimicrobial agents, including the novel molecule daptomycin, is presented. Multivariate analysis detects components or factors and establishes connections among antimicrobial agents on the basis of their different levels of participation in each factor. The first principal component was dominated by vancomycin, teicoplanin, and rifampin (0.94344, 0.92792, and 0.72127, respectively). The second principal component showed strong effects from imipenem, gentamicin, and cephalothin (0.87922, 0.86126, and 0.68870, respectively). Daptomycin stood out alone in the third principal component (0.83983). The first three components defined 81.5% of the total variance and could easily be represented graphically in a three-dimensional scatter plot. In this graphic representation, the eight antimicrobial agents clustered in three different spatial regions; daptomycin occupied a separate spatial position. The use of multivariate analysis offers a different approach to determination of the in vitro activities of new antimicrobial agents and adds some new data on the relationships among different classes. Notwithstanding its limitations, the application of these methods in microbiology and drug development could be an additional tool for use in processing information.

Anti-Bacterial Agents↗
PubMed1994

Bactericidal activities of peptide antibiotics against multidrug-resistant Enterococcus faecium.

Multidrug-resistant Enterococcus faecium has emerged as a serious pathogen for which no effective therapy has been established. In this report, we describe the activities of two peptide antibiotics, ramoplanin and daptomycin, against 15 isolates of E. faecium resistant to vancomycin, ampicillin, and aminoglycosides using time-kill experiments. Both antibiotics were rapidly bactericidal when tested in broth; however, the addition of 50% serum resulted in significant regrowth. The combination of ampicillin with either ramoplanin or daptomycin largely prevented this regrowth. These peptide antibiotics showed good activity against these pathogens. While the development of daptomycin has been halted, ramoplanin may hold promise for the therapy of multidrug-resistant E. faecium, especially when combined with ampicillin.

Ampicillin↗
PubMed2005

Nosocomial infections due to methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci at a university hospital in Taiwan from 1991 to 2003: resistance trends, antibiotic usage and in vitro activities of newer antimicrobial agents.

A rapid increase of nosocomial methicillin-resistant Staphylococcus aureus (MRSA) infection (from 39% in 1991 to 75% in 2003) and vancomycin-resistant enterococci (VRE) (from 1.2% in 1996 to 6.1% in 2003) at a university hospital in Taiwan was found. The noticeable rise of MRSA and VRE was significantly correlated with the increased consumption of glycopeptides, beta-lactam-beta-lactamase inhibitor combinations, extended-spectrum cephalosporins, carbapenems and fluoroquinolones (Pearson's correlation coefficient, P < 0.05). Minimum inhibitory concentrations (MICs) of 100 non-duplicate blood isolates of MRSA (in 2003) and of 25 non-duplicate isolates of vancomycin-resistant Enterococcus faecalis and 172 vancomycin-resistant Enterococcus faecium (in 1996-2003) causing nosocomial infection recovered from various clinical specimens of patients treated at the hospital to nine antimicrobial agents were determined by the agar dilution method. All of these isolates were susceptible to linezolid and were inhibited by 0.5mg/L of tigecycline, and all MRSA isolates were inhibited by daptomycin 1mg/L, including two isolates of MRSA with heteroresistance to vancomycin. Daptomycin had two-fold better activity against vancomycin-resistant E. faecalis (MIC90, 2 mg/L) than against vancomycin-resistant E. faecium (MIC90, 4 mg/L). Decreased susceptibilities of vancomycin-resistant E. faecium and MRSA to quinupristin/dalfopristin (non-susceptibility 25% and 8%, respectively) were found. Telithromycin had poor activity against the isolates tested (MIC90, 8 mg/L). Linezolid, daptomycin and tigecycline may represent therapeutic options for infections caused by these resistant Gram-positive organisms.

Anti-Bacterial Agents↗
PubMed1989

Treatment of experimental endocarditis caused by a beta-lactamase-producing strain of Enterococcus faecalis with high-level resistance to gentamicin.

Several antimicrobial regimens were evaluated in the treatment of experimental enterococcal endocarditis due to a beta-lactamase-producing, highly gentamicin-resistant strain of Enterococcus faecalis. Ampicillin alone cleared bacteremia in the majority of rats and reduced titers of bacteria within vegetations (6.84 versus 8.80 log10 CFU/g in controls) but did not sterilize valves. Ampicillin-sulbactam combinations, vancomycin, daptomycin, and imipenem each reduced residual bacterial titers within vegetations to 4.01 log10 CFU/g or less; in 26 to 43% of animals receiving 5 days of therapy, titers of bacteria were reduced to undetectable levels. In a separate experiment, rats received ampicillin-sulbactam, daptomycin, or vancomycin for 10 days and were then observed for 10 days after termination of therapy for evidence of relapse. In surviving rats, valves remained sterile in four of five rats treated with ampicillin-sulbactam, in five of seven treated with daptomycin, but in only one of eight receiving vancomycin.

Animals↗
PubMed2005

Vancomycin-resistant Enterococcus faecium: catheter colonization, esp gene, and decreased susceptibility to antibiotics in biofilm.

To evaluate the molecular characteristics and antibiotic susceptibility in biofilm of vancomycin-resistant Enterococcus faecium (VREF) organisms that had caused catheter-related VREF bacteremia (VREF-CRB), we compared 22 isolates causing bacteremia obtained from patients with VREF-CRB with 30 isolates from control patients with gastrointestinal colonization by VREF. Using pulsed-field gel electrophoresis, we identified 17 unique strains among the 22 VREF-CRB isolates and 23 strains among the gastrointestinal isolates. The esp gene was detected in 53% (9 of 17) of the VREF-CRB and 61% (14 of 23) of the control strains (P = 0.6). VREF-CRB produced heavier biofilm colonization of silicone disks than did control organisms (P < 0.001). Daptomycin, minocycline, and quinupristin-dalfopristin were each independently more active than linezolid in reducing biofilm colonization by VREF-CRB (P < 0.01), with daptomycin being the most active, followed by minocycline. In conclusion, the esp gene in VREF is not associated with heavy biofilm colonization or catheter-related bacteremia. In biofilm, daptomycin and minocycline were the most active antibiotics against VREF, and linezolid was the least active.

Anti-Bacterial Agents↗
PubMed2004

Newer treatment options for skin and soft tissue infections.

In recent years, serious skin and soft tissue infections (SSTIs) caused by multidrug resistant pathogens have become more common. While the majority of SSTIs are caused by Staphylococcus aureus or beta-haemolytic streptococci that are methicillin/oxacillin susceptible, the emergence of methicillin-resistant and vancomycin-resistant community-acquired and nosocomial Gram-positive pathogens has created a need for different therapeutic agents, such as linezolid, quinupristin/dalfopristin, daptomycin, and newer generation carbapenems and fluoroquinolones. This review focuses on agents presently in clinical development for the treatment of SSTIs caused by Gram-positive pathogens such as staphylococci, streptococci and enterococci including methicillin-resistant S. aureus (MRSA) and vancomycin-resistant enterococci (VRE). Newer-generation carbapenems, such as meropenem and ertapenem, are characterised by a broad-spectrum of activity against Gram-positive and -negative aerobes and anaerobes, and are resistant to hydrolysis by many beta-lactamases. Current-generation fluoroquinolones, such as levofloxacin, moxifloxacin and gatifloxacin, have demonstrated better eradication rates for S. aureus than conventional penicillin and cephalosporins. These antimicrobial agents can be used to treat methicillin-susceptible staphylococcal and streptococcal strains. Oxazolidinones, streptogramin combinations and cyclic lipopeptides have novel mechanisms of action and have been studied in several multinational phase III clinical trials in the treatment of complicated and uncomplicated SSTIs. They possess a broad spectrum of activity against multidrug-resistant pathogens, including MRSA and VRE. Linezolid has been shown to be active against a wide variety of community-acquired and nosocomial antimicrobial-resistant pathogens with comparability to vancomycin, as well as resulting in reduced lengths of hospital stay. Cyclic lipopeptides such as daptomycin have a unique mechanism of action by disruption of bacterial membrane electric potentials with less likelihood for development of cross-resistance. Daptomycin has recently been US FDA approved for the treatment of complicated SSTI. However, rapid development of resistance to some of these newer agents has already been reported and this trend magnifies the importance of further need for effective antimicrobial agents. Several investigational agents, such as dalbavancin, oritavancin and tigecycline, are in advanced stages of development and are likely to proceed to licensing in the next few years. With their long half-lives, these agents have an advantage of less frequent dose administration with more rapid bactericidal activity and less likelihood for development of resistance. However, because of their proven activity against highly resistant organisms, these antibacterial agents should be reserved only for life-threatening situations and/or when resistant pathogens are suspected. Rational antimicrobial use coupled with awareness of infection control measures is paramount to avert the emergence of multidrug-resistant organisms.

Anti-Bacterial Agents↗
PubMed1992

In vitro activity of the new glycopeptide decaplanin.

The activity of decaplanin, a new glycopeptide, was compared to that of vancomycin, teicoplanin and daptomycin. Decaplanin was two- to four-fold less active than vancomycin, telcoplanin and daptomycin against Staphylococcus aureus and Staphylococcus epidermidis, with an MIC90 of 2 micrograms/ml for methicillin-susceptible and 4 micrograms/ml for methicillin-resistant isolates. Decaplanin had activity similar to that of vancomycin against Streptococcus pyogenes, Streptococcus agalactiae, group C and G streptococci, with an MIC90 of 0.12 micrograms/ml. It was less active than the other agents against the viridans group streptococci (MIC90 4 micrograms/ml). The activity of decaplanin against enterococci (MIC90 4 micrograms/ml) was similar to that of vancomycin. Clostridium spp. were inhibited by 0.5 micrograms/ml, peptostreptococci and peptococci by 0.25 microgram/ml. Decaplanin was active from pH 5.5 to 7.5. Inoculum size had a minimal effect on MICs, and increased concentrations of Ca2+ and Mg2+ and 50% serum did not alter MICs or MBCs.

Anti-Bacterial Agents↗
PubMed2006

Use of antibiotic-loaded polymethylmethacrylate beads for the treatment of extracavitary prosthetic vascular graft infections.

PURPOSE: This study was conducted to assess the efficacy of antibiotic-loaded polymethylmethacrylate (PMMA) beads in the management of lower extremity extracavitary prosthetic arterial graft infection. METHODS: This was a retrospective review of 34 patients treated for vascular surgical site (VSS) infections involving 36 prosthetic lower extremity arterial bypasses using antibiotic-loaded PMMA beads and culture-specific parenteral antibiotics for 4 to 6 weeks. Sites of graft infection were explored, debrided, and cultured. As determined from the results of Gram's stains of VSS purulence, PMMA powder was polymerized with an antibiotic (vancomycin, daptomycin, or tobramycin/gentamicin, or a combination), molded into a chain of beads, and implanted adjacent to the infected graft after debridement and pulsed-spray antibacterial lavage. All wounds were closed primarily with planned exploration to verify sterilization before a graft preservation or in situ replacement procedure. Treatment outcomes, including wound sterilization, were analyzed based on tissue culture isolates, procedures for persistent infection, and freedom from graft infection. RESULTS: Cultures isolated 42 pathogens, (32 gram-positive, 9 gram-negative, 1 Candida albicans) with methicillin-resistant Staphylococcus aureus (MRSA) cultured from 16 (44%) of 36 surgical site infections. As determined from the initial operative Gram's stain or a prior culture result, vancomycin PMMA beads were implanted in 29 of 36 VSS infections at the first procedure; daptomycin (n = 4) or tobramycin (n = 3) beads were implanted in the rest. Repeat VSS exploration and culture results led to an average of 2.5 antibiotic bead replacements before definitive treatment. A sterile (no growth on tissue culture) VSS was achieved in 87% of cases before a graft preservation (n = 16) or in-situ replacement of an infected graft (n = 20) procedure. No patient deaths occurred. Early and late limb salvage was 100%. Infection recurred in 4 (11%) VSSs during a mean 23-month follow-up period, one within 3 months owing to unrecognized bowel injury associated with in situ replacement of an aortofemoral graft limb. CONCLUSION: Antibiotic-loaded PMMA beads may be a useful adjunct in the contemporary surgical management of VSS infection involving a prosthetic graft. Wound sterilization was achieved in most VSSs before graft preservation or an in-situ replacement procedure, including infections caused by MRSA, a pathogen isolated in half of the extracavitary prosthetic graft infections. This preliminary trial shows the potential benefit of this new technique, but further study is required to prove efficacy.

Aged↗
PubMed1997

Applications of transposition mutagenesis in antibiotic producing streptomycetes.

Several transposons have been developed from the streptomycete insertion sequence IS493. They have broad host specificity in Streptomyces species and insert relatively randomly into a consensus target sequence of gNCaNTgNNy. Collectively, they have specialized features that facilitate the following: cloning of DNA flanking insertions; physical mapping of insertions; construction of highly stable mutants; and efficient construction of mutant libraries. All of the transposons can be introduced into streptomycetes by conjugation from E. coli, and can be delivered by curing the temperature sensitive delivery plasmid. Tn5099 was used to physically map genes involved in daptomycin and red pigment production in Streptomyces roseosporus, and to clone daptomycin biosynthetic genes. Tn5099 was also used in Streptomyces fradiae to identify and clone a neutral genomic site for the insertion of a second copy of the tylF gene. Recombinants containing two copies of the tylF gene carried out the normally rate limiting conversion of macrocin to tylosin very efficiently, thus causing substantial increases in tylosin yield.

Anti-Bacterial Agents↗
PubMed2004

Recent advances in the treatment of infections due to resistant Staphylococcus aureus.

PURPOSE OF REVIEW: This paper reviews recent data on the treatment of infections caused by drug-resistant Staphylococcus aureus, particularly methicillin-resistant S. aureus (MRSA). This review will focus on new findings reported in the English-language medical literature from June 2003 to September 2004. RECENT FINDINGS: Despite the emergence of resistant and multidrug-resistant S. aureus, we have three effective drugs in clinical use for which little resistance has been observed: quinupristin-dalfopristin, linezolid, and daptomycin. Linezolid looks particularly promising in the treatment of MRSA pneumonia. Daptomycin displays rapid bactericidal activity in vitro, but, so far, clinical trials have only been conducted for the treatment of skin and soft-tissue infections. There are three drugs with broad-spectrum activity against Gram-positive organisms at an advanced stage of testing: two new glycopeptides with potent bacteriocidal activity and long half-lives (oritavancin and dalbavancin), and tigecycline, a minocycline derivative. These drugs have also shown efficacy in the treatment of skin and soft-tissue infections. SUMMARY: The promising data that have emerged in the last year indicate that we may have six available drugs to treat resistant S. aureus infections within the next few years. The next goal is to determine the appropriate indications and cost-effectiveness of each of these drugs in our treatment strategy against S. aureus and other Gram-positive pathogens.

Acetamides↗
PubMed2005

New antibiotics for the treatment of severe staphylococcal infection in the critically ill patient.

PURPOSE OF REVIEW: Infection by Staphylococcus aureus in critically ill patients is usually associated with antimicrobial resistance and high mortality. A more effective antibiotic treatment is needed to replace older drugs that have limited efficacy. Novel substances active on methicillin-resistant Staphylococcus aureus, which are already available on the market or are still in development, are discussed in this review, with emphasis on nosocomial infections. RECENT FINDINGS: A number of new antibiotics are on the market (linezolid, quinupristin-dalfopristin, daptomycin) and there is good evidence regarding their efficacy, especially in methicillin-resistant Staphylococcus aureus infections. Linezolid is, to date, the best alternative in treating nosocomial pneumonia by methicillin-resistant Staphylococcus aureus. It is cost-effective; resistance levels are still very low but there are some concerns regarding its adverse events. Quinupristin-dalfopristin shows good activity in vitro but its efficacy in patients with pneumonia by methicillin-resistant Staphylococcus aureus is modest. Daptomycin is not recommended for pulmonary infections because of its reduced penetration in the lung tissue. Under current phase III trials in patients with nosocomial infections are tigecycline, ceftobiprole, and three new glycopeptides, all with particular activity against methicillin-resistant Staphylococcus aureus. SUMMARY: For the moment, there are limited and rather expensive therapeutic options for the infections by Staphylococcus aureus in the critically ill. No dramatic superiority of the new drugs in comparison to the standard therapies was observed in most of the clinical trials. Better results on the efficacy of the drugs under investigation are expected.

Acetamides↗
PubMed2005

Efficacy of current agents used in the treatment of Gram-positive infections and the consequences of resistance.

The proportion of pathogens causing hospital-onset infections that are resistant to antimicrobial agents continues to increase worldwide. Inadequate antimicrobial therapy is an important factor in the emergence of resistance and is associated with increased mortality. In the USA in 2000, the National Nosocomial Infections Surveillance system reported that >50% of Staphylococcus aureus isolates collected from intensive care units were resistant to methicillin (MRSA). The emergence of community-acquired MRSA is a new concern. MRSA are associated with adverse clinical outcomes and increased hospital costs. The increasing prevalence of MRSA contributes to the use of glycopeptides; however, isolates with intermediate and full resistance to vancomycin and teicoplanin are now being reported. Newer agents, such as the oxazolidinone linezolid, are effective in the treatment of serious Gram-positive infections; however, linezolid-resistant isolates of Enterococcus faecium, Enterococcus faecalis and S. aureus have been reported. Therefore, there is an unmet clinical need for new agents with activity against Gram-positive pathogens. Daptomycin, a lipopeptide with a novel mode of action, was recently approved for the treatment of skin and soft tissue infections in the USA. The two case studies presented herein detail experience with the use of daptomycin in the USA.

Acetamides↗
PubMed1990

In vitro response to bactericidal activity of cell wall-active antibiotics does not support the general opinion that enterococci are naturally tolerant to these antibiotics.

The incidence of tolerance and paradoxical response to bactericidal activity of penicillin was investigated in 50 clinical isolates of Enterococcus faecalis. Of the isolates tested, 86% exhibited the paradoxical phenomenon whereby there were more survivors at high than at low concentrations above the MIC. Low penicillin concentrations caused decreases equal to or higher than 99.9% in 11 strains, from 99.9 to 99.5% in 23 strains, and lower than 99.5% in 9 strains. Of the total strains, 14% were killed to the same extent by all concentrations above the MIC. The bactericidal activities of other beta-lactams (ampicillin and piperacillin) and other cell wall inhibitors (vancomycin and daptomycin) were also tested against some of these strains. In general, beta-lactams exhibited the best bactericidal activity at 2 x MIC. Piperacillin was the most active, as at 2 x MIC it reduced the original inoculum by 99.9% or more in most of the strains. No concentration of vancomycin above the MIC caused 99.9% killing of the strains, whereas daptomycin was bactericidal at 8 x MIC in most cases. Paradoxical response to bactericidal activity of beta-lactams was abolished by incubation of the inoculum with 2 x MIC before exposure to higher antibiotic concentrations. These findings suggest that enterococci are not always tolerant to cell wall-active antibiotics and that accurate in vitro bactericidal tests may be useful for the choice of appropriate therapy for infections caused by these microorganisms.

Ampicillin↗
PubMed1992

Susceptibility testing of clinical isolates of Enterococcus faecium and Enterococcus faecalis.

We collected 103 clinical Enterococcus faecium isolates from across Canada, performed standard broth microdilution susceptibility testing, and compared these results with results from the MicroScan Pos MIC Type 6 panel (Baxter Health Care Corp., West Sacramento, Calif.) and the AMS-Vitek Gram-Positive Susceptibility card (Vitek Inc., St. Louis, Mo.). High-level aminoglycoside resistance to gentamicin and streptomycin was detected by a single-concentration agar method with 1,000 micrograms of each aminoglycoside per ml. In addition, we tested the effect of the lower calcium content in broth media as recommended in National Committee for Clinical Laboratory Standards (NCCLS) guideline M7-A2 on the activity of the highly calcium-dependent agent daptomycin. Of the 103 E. faecium isolates, there were 4 and 30 isolates with high-level gentamicin resistance (HLGR) and high-level streptomycin resistance (HLSR), respectively. An additional 39 (37 with HLGR and 36 with HLSR) E. faecium isolates were tested by both the MicroScan and the AMS-Vitek systems. The AMS-Vitek card demonstrated sensitivities of 95 and 82% for detecting HLGR strains and HLSR strains, respectively. The MicroScan panel demonstrated improved sensitivities for detecting HLGR (42 to 97%) and HLSR (64 to 84%) when readings were performed manually instead of being generated automatically. Ampicillin resistance (MIC, greater than or equal to 16 micrograms/ml) was detected in 23 of the 103 E. faecium isolates. Only 14 and 20 of these were detected by the MicroScan panels and AMS-Vitek cards, respectively. beta-Lactamase activity was not detected in any isolates. The lower calcium content in broth media recommended by NCCLS guideline M7-A2 markedly reduced the in vitro activity of daptomycin against Enterococcus spp.

Calcium↗
PubMed1992

Pharmacodynamic effects of antibiotics. Studies on bacterial morphology, initial killing, postantibiotic effect and effective regrowth time.

Pharmacodynamics of antibiotics deals with time course of drug activity and mechanisms of action of drugs on bacteria. In this thesis pharmacodynamic parameters have been studied after brief exposure of gram-positive bacteria to daptomycin, imipenem or vancomycin and after short exposure of gram-negative bacteria to amikacin, ampicillin, aztreonam, cefepime, cefotaxime, ceftazidime, ceftriaxone, cefuroxime, imipenem, mecillinam, or piperacillin. The studies have been focused on morphological alterations, initial killing, postantibiotic effect (PAE) and effective regrowth time (ERT) and a method, based on bioluminescence assay of intracellular ATP has been used. The basic principle behind this technique is that ATP in living cells is present in a relatively constant amount, and hence affords a measure of the number of microbial cells. The PAE describes the delayed regrowth of bacteria after brief exposure to antibiotics. The number of cells measured after this antibiotic exposure describes the initial killing and is also the start value for calculating the PAE. PAEs of 2-3 h were obtained by bioluminescence for gram-positive bacteria exposed to imipenem or vancomycin. This is in agreement with results obtained by viable count and is probably due to similar weak initial decrease in cell density when assayed by both methods. Long (greater than 3 h) concentration dependent PAEs and moderate (less than or equal to 1 log10) initial decrease in intracellular ATP were in general seen for gram-positive bacteria exposed to daptomycin and for gram-negative bacteria exposed to imipenem or amikacin when assayed by bioluminescence. These very long PAEs and rather weak initial killing have to be compared with the shorter PAEs and stronger initial killing reported by us and others using viable count. Furthermore, this study showed that there was a relatively good concordance between microscopy and bioluminescence, which are direct methods, in determining the initial killing and PAE of imipenem on Escherichia coli. The ERT, defined as the time for bacterial density to increase 1 log10 from the pre-exposure inoculum, was independent of the method used for measuring regrowth of E. coli after brief exposure to imipenem. The combination of mecillinam with ampicillin, aztreonam, ceftazidime or piperacillin and the combination of amikacin with ceftazidime, ceftriaxone or piperacillin induced longer PAEs on gram-negative bacteria than the sum of PAEs of the individual antibiotics. A strong initial killing in combination with a long PAE cause a long ERT and may allow the antibiotic concentration to stay below MIC during long periods of time without any regrowth. This may, in clinical practice, have implications for long dosing intervals.

Amdinocillin↗
PubMed1991

New targets for the mechanism of action of antibiotics active against gram-positive cocci.

The main mechanisms of resistance to beta-lactams in gram-positive cocci include either the production of beta-lactamases or alterations in the molecular targets of these antibiotics, the penicillin binding proteins (PBPs). In spite of the appearance of new beta-lactams, more stable to the hydrolytic activity of beta-lactamases or with higher affinity for PBPs, no substantial progress in improving the activity against gram-positive has been achieved. In addition to the search for new beta-lactams it would be of interest to find molecules directed against new targets of the cell wall of gram-positive bacteria (i.e. teichoic acids and lipoteichoic acid) of which up to now no specific inhibitor is known. These two wall polymers are thought to be essential for cell survival within the host. Among new inhibitors a new antibiotic belonging to the class of acid lipopeptides called daptomycin (LY146032), and active against gram-positive seems of particular interest. Our studies demonstrate that daptomycin is a specific inhibitor of lipoteichoic acid synthesis.

Anti-Bacterial Agents↗
PubMed2006

Viridans group streptococci in blood culture isolates in a Swedish university hospital: antibiotic susceptibility and identification of erythromycin resistance genes.

One hundred and twenty-nine isolates of viridans group streptococci in blood cultures from patients with septicaemia or endocarditis isolated between 1998 and 2003 were tested for antibiotic susceptibility to penicillin, ciprofloxacin, clindamycin, dalbavancin, daptomycin, erythromycin, linezolid, tigecycline, trimethoprim/sulphamethoxazole and vancomycin. Reduced susceptibility to penicillin (minimum inhibitory concentration (MIC) > or =0.25 microg/mL) was found in 18% of the isolates, and 4% of the strains were resistant to penicillin (MIC> or =4.0 microg/mL). Nineteen percent of the isolates had reduced susceptibility to erythromycin (MIC> or =0.5 microg/mL), among which ermB and mefA were found in 40% and 80%, respectively. Strains sequenced as Streptococcus mitis by rnpB had a high degree of non-susceptibility to erythromycin (32%) and penicillin (21%). The level of penicillin resistance in this Swedish study was lower compared with studies from other countries where the antibiotic pressure might be higher than in Sweden. Susceptibility to newer antibiotics was high; all strains were susceptible to dalbavancin, daptomycin, linezolid and vancomycin.

Blood↗
PubMed2006

Biosynthesis of the (2S,3R)-3-methyl glutamate residue of nonribosomal lipopeptides.

The calcium-dependent antibiotics (CDAs) and daptomycin are therapeutically relevant nonribosomal lipopeptide antibiotics that contain penultimate C-terminal 3-methyl glutamate (3-MeGlu) residues. Comparison with synthetic standards showed that (2S,3R)-configured 3-MeGlu is present in both CDA and daptomycin. Deletion of a putative methyltransferase gene glmT from the cda biosynthetic gene cluster abolished the incorporation of 3-MeGlu and resulted in the production of Glu-containing CDA exclusively. However, the 3-MeGlu chemotype could be re-established through feeding synthetic 3-methyl-2-oxoglutarate and (2S,3R)-3-MeGlu, but not (2S,3S)-3-MeGlu. This indicates that methylation occurs before peptide assembly, and that the module 10 A-domain of the CDA peptide synthetase is specific for the (2S,3R)-stereoisomer. Further mechanistic analyses suggest that GlmT catalyzes the SAM-dependent methylation of alpha-ketoglutarate to give (3R)-methyl-2-oxoglutarate, which is transaminated to (2S,3R)-3-MeGlu. These insights will facilitate future efforts to engineer lipopeptides with modified glutamate residues, which may have improved bioactivity and/or reduced toxicity.

Chromatography, Liquid↗