Drug-resistant Gram-positive Bacteria Research Articles

Ultraviolet-C Irradiation for Prevention of Central Venous Catheter-related Infections: An In Vitro Study

Central venous catheters (CVC) are widely used in the United States and are associated with 250,000 to 500,000 CVC-related infections in hospitals annually. We used a catheter made from ultraviolet-C (UVC) transmissive material to test whether delivery of UVC from the lumen would allow inactivation of microorganisms on the outer surface of CVC. When the catheter was exposed to UVC irradiation from a cold cathode fluorescent lamp inside the catheter lumen at a radiant exposure of 3.6 mJ cm(-2) , more than 6-log(10) of drug-resistant Gram-positive bacteria adhered to the outer surface of the catheter were inactivated. Three to 7-log(10) of drug-resistant Gram-negative bacteria and 2.80-log(10) of fungi were inactivated at a radiant exposure of 11 mJ cm(-2).UVC irradiation also offered a highly selective inactivation of bacteria over keratinocytes under exactly comparable conditions. After 11 mJ cm(-2) UVC light had been delivered, over 6-log(10) of bacteria were inactivated while the viability loss of the keratinocytes was only about 57%.

Bottromycin derivatives: Efficient chemical modifications of the ester moiety and evaluation of anti-MRSA and anti-VRE activities

Novel bottromycin derivatives were synthesized from bottromycin A 2 via a hydrazide derivative as a common intermediate. Seventeen derivatives were subjected to in vitro evaluation against drug-resistant gram-positive bacteria. Some compounds showed potent anti-MRSA and anti-VRE activity, as did bottromycin A 2. Notably, a propyl ketone derivative exhibited good antibacterial activity with excellent metabolite stability.

Plectasin, a Fungal Defensin, Targets the Bacterial Cell Wall Precursor Lipid II

Host defense peptides such as defensins are components of innate immunity and have retained antibiotic activity throughout evolution. Their activity is thought to be due to amphipathic structures, which enable binding and disruption of microbial cytoplasmic membranes. Contrary to this, we show that plectasin, a fungal defensin, acts by directly binding the bacterial cell-wall precursor Lipid II. A wide range of genetic and biochemical approaches identify cell-wall biosynthesis as the pathway targeted by plectasin. In vitro assays for cell-wall synthesis identified Lipid II as the specific cellular target. Consistently, binding studies confirmed the formation of an equimolar stoichiometric complex between Lipid II and plectasin. Furthermore, key residues in plectasin involved in complex formation were identified using nuclear magnetic resonance spectroscopy and computational modeling.

Defining Defensins' Mode of Action

Defensins are antimicrobial host defense peptides that play a role in innate immunity. Many such peptides act by disrupting the bacterial membrane; however, Schneider et al. (p. [1168][1]) now show that the fungal defensin, plecstasin, targets cell wall biosynthesis. Biochemical studies identified Lipid II as the cellular target of plecstasin and the residues involved in complex formation were identified using NMR spectroscopy and computational modeling. Initial studies identified two defensins from invertebrates that also target Lipid II. Plecstasin is active against some drug-resistant Gram-positive bacteria, and its action against a validated target makes it a promising lead for further drug development. [1]: /lookup/doi/10.1126/science.1185723

Microbiology of drugs for treating multiply drug-resistant Gram-positive bacteria

Several new antimicrobials demonstrate in vitro activity against methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE), and other Gram-positive bacteria. Data from large surveys indicate that linezolid, daptomycin, and tigecycline are almost universally active against MRSA. Linezolid and tigecycline inhibit both Enterococcus faecium and Enterococcus faecalis at low concentrations; daptomycin is somewhat more potent against the latter. The investigational agents dalbavancin and telavancin are more potent than vancomycin against vancomycin-susceptible organisms. Dalbavancin inhibits vanB type VRE at low concentrations, but is not active against vanA type VRE. Telavancin is less active against VRE than against vancomycin-susceptible enterococci, but minimum inhibitory concentrations are lower than those of vancomycin against VRE. With continued careful use of available antimicrobials, the vast majority of these organisms should remain susceptible to 1 or more of the agents discussed for the foreseeable future.

Polymeric N-Halamine Latex Emulsions for Use in Antimicrobial Paints

A new N-halamine monomer, N-chloro-2,2,6,6-tetramethyl-4-piperidinyl methacrylate (Cl-TMPM), was synthesized and used to prepare water-based polymeric N-halamines by emulsion polymerization. The chemical structures of the samples were characterized with Fourier transform IR, (13)C NMR, UV/vis, and differential scanning calorimetry analyses. Upon the addition of a small amount of the polymeric N-halamine latex emulsions into commercial water-based latex paints as antimicrobial additives, the new paints provided potent antimicrobial activities against Staphylococcus aureus (S. aureus; Gram-positive bacteria), methicillin-resistant S. aureus (MRSA; drug-resistant Gram-positive bacteria), vancomycin-resistant enterococcus (VRE; drug-resistant Gram-positive bacteria), Escherichia coli (E. coli; Gram-negative bacteria), Candida tropicalis (C. tropicalis; fungi), MS2 virus (15597-B; virus), and Stachybotrys chartarum spore (S. chartarum; mold), and they successfully prevented biofilm formation and development. The antimicrobial functions of the new paints were long-lasting for more than 1 year under normal in-use conditions, easily monitorable by a simple potassium iodine/starch test, and readily rechargeable if the functions were accidentally lost as a result of challenging conditions such as heavy soil, flooding, etc.

Linezolid for treatment of catheter-related cerebrospinal fluid infections in preterm infants

Ventriculostomy-related cerebrospinal fluid (CSF) infection remains a major problem in neonatal intensive care. The spectrum of pathogens causing these infections is dominated by coagulase-negative staphylococci, and vancomycin is the antibiotic...

Comment on “Surviving Sepsis Campaign: International guidelines for management of severe sepsis and septic shock: 2008” by Dellinger et al.

Comment on “Surviving Sepsis Campaign: International guidelines for management of severe sepsis and septic shock: 2008” by Dellinger et al.

The management of infections due to drug-resistant gram-positive bacteria

The management of infections due to drug-resistant gram-positive bacteria

Discovery of a potent phenolic N1-benzylidene–pyridinecarboxamidrazone selective against Gram-positive bacteria

As part of a study into antimycobacterial compounds a set of phenolic N 1-benzylidene–pyridinecarboxamidrazones was prepared and evaluated. This report describes the unexpected discovery of a potent compound with a pronounced selectivity for Gram-positive bacteria over Gram-negative micro-organisms. In addition, this compound is active against various drug-resistant Gram-positive bacteria.

DNA binding ligands targeting drug-resistant Gram-positive bacteria. Part 2: C-terminal benzimidazoles and derivatives

The synthesis and in vitro potency of DNA minor-groove binding antibacterials lacking the C-terminal amide bond are described. The crescent shaped molecules bear the positively charged amino group at an internal pyrrole unit instead of the C-terminus. Three structural parameters were investigated: the N-terminal unit, the internal amino group, and the C-terminal ring system. Several compounds demonstrated good in vitro potency against various Gram-positive bacteria and some molecules were moderately active against Escherichia coli, a representative Gram-negative strain.

DNA binding ligands targeting drug-resistant Gram-positive bacteria. Part 1: Internal benzimidazole derivatives

Novel DNA minor-groove binding ligands with a promising antibacterial profile are described. Apart from excellent in vitro potency against multiple Gram-positive bacterial strains such as methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus faecalis (VRE), and penicillin-intermediate Streptococcus pneumoniae (PISP), a small subset of compounds was active against Gram-negative bacteria such as Escherichia coli (E. coli).

Clinical Outcome with Oral Linezolid and Rifampin Following Recurrent Methicillin‐Resistant Staphylococcus aureus Bacteremia Despite Prolonged Vancomycin Treatment

Drug-resistant Gram-positive bacteria, especially Staphylococcus aureus, are emerging as the predominant organisms involved in both nosocomial and community-acquired infections. Since the 1980s, vancomycin has been the first-line antibiotic used to treat methicillin- resistant S aureus. However, allergy and intolerance to vancomycin, the increasing number of vancomycin clinical failures and the existence of vancomycin intermediate-susceptible isolates of S aureus suggest that new antibiotics are needed. This paper reports the only known case of a successful clinical outcome with long term oral linezolid and rifampin therapy in the management of recurrent and persistent methicillin-resistant S aureus bacteremia with metastatic infections despite prolonged vancomycin use. More than two years since the initiation of linezolid and rifampin, the study patient has been clinically well with no evidence of adverse drug reactions including cytopenia and hepatic toxicities. Physicians must be aware of the novel developments in antibiotic therapy to treat drug-resistant bacterial infections.

Opsonic activity assessment of human intravenous immunoglobulin preparations against drug-resistant bacteria.

We have used the ability of opsonized bacteria to stimulate luminol-enhanced chemiluminescence (CL) of human polymorphonuclear leukocytes (PMN) to examine the opsonic capabilities of commercially available human intravenous immunoglobulin (i.v.Ig) preparations. The method was tested against 14 strains of drug-resistant gram-positive bacteria (including methicillin-resistant Staphylococcus aureus, hetero-vancomycin-resistant S. aureus, vancomycin-resistant enterococci, penicillin-resistant Streptococcus pneumoniae), and 23 strains of gram-negative bacteria (including extended-spectrum beta-lactamase-producing bacteria, metallo-beta-lactamase-producing bacteria, beta-lactamase-negative ampicillin-resistant Haemophilus influenzae). An Fc-intact i.v.Ig preparation treated with polyethylene glycol (PEG) was evaluated for opsonization effectiveness against these bacteria in vitro. The opsonization of these organisms was enhanced by an Fc-intact i.v.Ig, and the opsonic activity was dose dependent. A pepsin-treated i.v.Ig preparation exhibited poor opsonic activity for all bacteria tested. These results suggest that Fc-intact i.v.Ig, which augments opsonic activity against various drug-resistant bacteria, will be a useful addition to the treatment of severe bacterial infections in immunocompromised patients with impaired serum opsonic capacity.

DNA Binding Ligands with Excellent Antibiotic Potency Against Drug-Resistant Gram-Positive Bacteria

An efficient synthesis of DNA binding molecules consisting of four heterocyclic carboxamide units and various substituents at both termini is described. The minor-groove binding ligands showed excellent activity against a broad range of Gram-positive bacteria; no cross-resistance to known antibacterial drugs was observed.

Functional Analysis of the Lipoglycodepsipeptide Antibiotic Ramoplanin

The peptide antibiotic ramoplanin is highly effective against several drug-resistant gram-positive bacteria, including vancomycin-resistant Enterococcus faecium (VRE) and methicillin-resistant Staphylococcus aureus (MRSA), two important opportunistic human pathogens. Ramoplanin inhibits bacterial peptidoglycan (PG) biosynthesis by binding to Lipid intermediates I and II at a location different than the N-acyl-D-Ala-D-Ala dipeptide site targeted by vancomycin. Lipid I/II capture physically occludes these substrates from proper utilization by the late-stage PG biosynthesis enzymes MurG and the transglycosylases. Key structural features of ramoplanin responsible for antibiotic activity and PG molecular recognition have been discovered by antibiotic semisynthetic modification in conjunction with NMR analyses. These results help define a minimalist ramoplanin pharmacophore and introduce the possibility of generating ramoplanin-derived peptide or peptidomimetic antibiotics for use against VRE, MRSA, and related pathogens.

Carbon–carbon-linked (pyrazolylphenyl)oxazolidinones with antibacterial activity against multiple drug resistant gram-positive and fastidious gram-negative bacteria

In an effort to expand the spectrum of activity of the oxazolidinone class of antibacterial agents to include Gram-negative bacteria, a series of new carbon–carbon linked pyrazolylphenyl analogues has been prepared. The α- N-substituted methyl pyrazole ( 10α) in the C3-linked series exhibited very good Gram-positive activity with MICs ≤0.5–1 μg/mL and moderate Gram-negative activity with MICs=2–8 μg/mL against Haemophilus influenzae and Moraxella catarrhalis. This analogue was also found to have potent in vivo activity with an ED 50=1.9 mg/kg. β-Substitution at the C3-linked pyrazole generally results in a loss of activity. The C4-linked pyrazoles are slightly more potent than their counterparts in the C3-linked series. Most of the analogues in the C4-linked series exhibited similar levels of activity in vitro, but lower levels of activity in vivo than 10α. In addition, incorporation of a thioamide moiety in selected C4-linked pyrazole analogues results in an enhancement of in vitro activity leading to compounds several times more potent than eperezolid, linezolid and vancomycin. The thioamide of the N-cyanomethyl pyrazole analogue ( 34) exhibited an exceptional in vitro activity with MICs of ≤ 0.06–0.25 μg/mL against Gram-positive pathogens and with MICs of 1 μg/mL against fastidious Gram-negative pathogens.

Postoperative infections in the age of drug-resistant gram-positive bacteria

Postoperative infection is a significant cause of surgical morbidity and mortality. The risk of infection after surgery depends on a number of factors, including the type and length of the surgical procedure; the age, underlying conditions, and previous history of the patient; the skill of the surgeon; the diligence with which infection control procedures are applied; and the type and timing of preoperative antibiotic prophylaxis. Methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci, now implicated in many postoperative infections, have been joined most recently by strains of S. aureus that show intermediate levels of resistance to vancomycin. Postoperative infections caused by drug-resistant pathogens are more difficult to treat and are associated with a higher morbidity and mortality. New antibiotics that are effective against drug-resistant pathogens are urgently needed, as is renewed dedication to the prevention of postoperative infection and to the use of the principles of infection control.

Resistant microbes on the rampage - can anything be done?

The increase in drug-resistant Gram-positive bacteria, such as methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci, was a major concern aired at the 19th International Congress of Chemotherapy [ Montreal, Canada; July 1995 ]. Outbreaks of MRSA infection have been recorded in hospitals the world over. Although there were high hopes that new classes of drugs, such as the quinolones, would help defeat this organism, MRSA resistance to various quinolones now appears to be widespread. But all is not lost. According to data presented at the congress, infection can be prevented with appropriate control measures, and new drugs with activity against MRSA, vancomycin-resistant enterococci and other resistant organisms are under investigation.