Resistant Gram-positive Bacteria Research Articles

Pleuromutilin derivatives having a purine ring. Part 3: Synthesis and antibacterial activity of novel compounds possessing a piperazine ring spacer

SAR studies on the water-soluble thioether pleuromutilin analogue 6, which has excellent in vitro and in vivo antibacterial activities, led to discovery of the novel pleuromutilin derivatives having a piperazine ring spacer. These derivatives displayed potent and well-balanced in vitro antibacterial activity against various drug-susceptible and -resistant Gram-positive bacteria. In particular, the promising pleuromutilin analogues 37 and 40 were found to exhibit strong in vivo efficacy against Staphylococcus aureus Smith.

Tigecycline In-vitro Surveillance in Taiwan (TIST)

The last half of the 20th century has seen significant progress in the development of antibacterial agents. This progress fostered the perception that bacterial diseases were more readily cured than any other major disorder. However, in the last decade, the emergence of multidrug-resistant organisms has resulted in serious public health implications. Currently, resistance has spread to previously susceptible organisms, and some organisms are essentially resistant to all approved antibacterial agents. In Taiwan, the strikingly high prevalence of resistance to macrolides and streptogramin in clinical isolates of Grampositive bacteria correlates with the widespread use of these agents in the medical and farming communities, respectively. The increasing rate of enterococci that are resistant to glycopeptides does parallel the high use of glycopeptides and extended-spectrum b-lactams in hospitals. The evolving problem of extended-spectrum b-lactamase (ESBL)-producing Escherichia coli and Klebsiella pneumoniae isolates is substantial, and some unique enzymes have been reported. Recently, some Gram-negative bacteria (e.g., Pseudomonas aeruginosa, Acinetobacter baumannii and Stenotrophomonas maltophilia) that are resistant to nearly all available antimicrobial agents (susceptible to only polymyxin B or E [colistin] or tigecycline) have become widespread in the hospitals. Tigecycline is a glycylcycline antibiotic and an analog of the semisynthetic tetracycline, minocycline. This agent was developed in order to restore therapeutic utility to this tetracycline class by overcoming tetracycline resistance mechanisms. It demonstrates a broad spectrum of antibacterial activity by inhibiting multiple resistant Gram-positive, Gramnegative, anaerobic, and atypical bacteria. Tigecycline does not demonstrate significant in-vitro activity against Pseudomonas aeruginosa, Proteus species, or Providencia species. Tigecycline has shown to be efficacious in a variety of animal models of infections. This agent has been approved for clinical use for intra-abdominal infection and skin and skinstructure infections in humans. Investigators from 20 major hospitals in Taiwan are participating in a multi-center surveillance study to demonstrate the in-vitro potency of tigecycline against a wide variety of pathogens from both nosocomial and communityacquired infections, using the disk diffusion method, the Etest (Epsilometer test), and the broth microdilution method in Taiwan. This study will be completed in approximately five years (2006 2010). Up to 20,100 isolates in total (3,000 isolates in year 2006; 3,000 isolates in year 2007; up to 4,700 isolates in each year from 2008 to 2010) will be collected in this study. For the years 2006 2007, each site will collect approximately 150 isolates per year. For the years 2008 2010, each site will collect up to 235 isolates per year. All the isolates are clinically relevant organisms (no duplicates) and must meet the laboratory criteria of “significant pathogens” and be considered the “probable causative agents” of hospitalor communityacquired infections. Minimum inhibitory concentrations (MICs) are determined by the Etest (Epsilometer test) and the disk diffusion method at each site’s laboratory; determination by the broth microdilution method is performed at the central laboratory (National Taiwan University Hospital). The purpose of this study is to determine the in-vitro activity of tigecycline against a variety of resistant Gram-positive and -negative bacteria from patients with various clinical infections in Taiwan. This study also aims to evaluate the suitability of three susceptibility testing methods for routine use in clinical microbiology laboratories.

Design at the atomic level: Design of biaryloxazolidinones as potent orally active antibiotics

We have developed a first generation of hybrid sparsomycin–linezolid compounds into a new family of orally bioavailable biaryloxazolidinones that have activity against both linezolid-susceptible and -resistant Gram-positive bacteria as well as the fastidious Gram-negative bacteria Haemophilus influenzae and Moraxella catarrahalis. The convergent synthesis of these new compounds is detailed.

Current and novel antibiotics against resistant Gram-positive bacteria

The challenge posed by resistance among Gram-positive bacteria, epitomized by methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus (VRE) and vancomycin-intermediate and -resistant S. aureus (VISA and VRSA) is being met by a new generation of antimicrobials. This review focuses on the new β-lactams with activity against MRSA (ceftobiprole and ceftaroline) and on the new glycopeptides (oritavancin, dalbavancin, and telavancin). It will also consider the role of vancomycin in an era of existing alternatives such as linezolid, daptomycin and tigecycline. Finally, compounds in early development are described, such as iclaprim, friulimicin, and retapamulin, among others.

Therapeutic options for the treatment of infections with multiresistant grampositive bacteria in oncological patients

Infections with highly resistant grampositive bacteria are a major threat to the patients with underlying malignant diseases and due to more aggressive treatment strategies the incidence of these infections increased over the past years. For many years, glycopeptides such as vancomycin, have been the standard treatment for methicillin-resistant S. aureus (MRSA) and ampicillin-resistant enterococci. However, the clinical use of vancomycin may be limited by the adverse effects like poor tissue penetration and the emergence of vancomycin-resistant strains such as vancomycin-resistant enterococci and staphylococci. Thus, in recent years, new antimicrobial agents have been introduced into clinical praxis or are under investigation. This review summarizes current clinical data on novel therapeutics such as linezolid, tigecycline and daptomycin as well as investigational new drugs. Linezolid, an oxazolidinone derivative, has proven clinical activity only against infections with grampositive bacteria including vancomycin-resistant rods. Tigecycline is a tetracycline derivative with a very broad antimicrobial spectrum including multiresistant grampositive strains. Daptomycin, belonging to a new class of cyclic lipopeptide antibiotics, is approved for the treatment of skin and skin-structure infections, bactermia and endocarditis with grampositive bacteria. However, only limited data exist on the clinical use of tigecycline and daptomycin in oncological patients. In the near future, novel cephalosporins and carbapenems with activity against MRSA as well as new semisynthetic glycopeptides will extend our therapeutic possibilities in the treatment of infections by multiresistant grampositive bacteria.

Proving the antimicrobial spectrum of an amphoteric surfactant-sol-gel coating: a food-borne pathogen study

An antimicrobial coating was evaluated in this work for its antimicrobial efficacy against common food-borne pathogens. Dodecyl-di(aminoethyl)-glycine, an organic disinfectant, was immobilized in a silicon oxide matrix to generate thin films over surfaces by means of the sol-gel process. Tetraethoxysilane was used as the polymeric precursor. No alteration of optical transparency on the covered surfaces was observed. Topographic images obtained with atomic force microscopy showed a homogeneous film with no additional roughness added by the polymer to the surface. The attenuated total reflectance-Fourier transform infrared spectral data showed the presence of dodecyl-di(aminoethyl)-glycine in the silicon oxide network after a normal cleaning procedure. The antimicrobial efficacy test was performed by exposing coated slides to suspensions of common food-borne pathogens: Escherichia coli, Staphyloccocus aureus, E. coli O157:H7, Salmonella typhi, S. cholerasuiss, Listeria innocua and L. monocytogenes. The coating activity was not only bacteriostatic but also bactericidal. The percent reduction of viable microorganism exposure over 24 h to the coated surface ranged between 99.5%, for the more resistant gram-positive bacteria, and over 99.999%, for most gram-negative bacteria. The silicon matrix itself did not account for any reduction of viable microbial, even more an increase was observed.

In Vitro Activity of Telavancin against Resistant Gram-Positive Bacteria

The in vitro activity of telavancin was tested against 743 predominantly antimicrobial-resistant, gram-positive isolates. Telavancin was highly active against methicillin-resistant staphylococci (MIC(90), 0.5 to 1 microg/ml), streptococci (all MICs, < or =0.12 microg/ml), and VanB-type enterococci (all MICs, < or =2 microg/ml). Time-kill studies demonstrated the potent bactericidal activity of telavancin.

In Vitro Antibacterial Activity of CE-156811, a Novel Analog Derived from Hygromycin A

We evaluated a novel truncated hygromycin A analog in which the furanose ring was replaced with a 2-fluoro-2-cyclopropylethyl substituent for its activity against multidrug resistant gram-positive bacteria and compared its activity to the activities of linezolid, quinupristin-dalfopristin, and vancomycin. CE-156811 demonstrated robust in vitro activity against gram-positive bacteria that was comparable to that of linezolid.

Daptomycin Therapy for Invasive Gram-Positive Bacterial Infections in Children

Clinical improvement is often delayed among children with invasive infections caused by multidrug resistant Gram-positive bacteria such as methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE) despite use of standard antimicrobial therapy. Daptomycin, a bactericidal lipopeptide antibiotic, may prove useful for treatment of these infections in children, but clinical experience is lacking. Retrospective review of medical records of hospitalized children who received daptomycin for treatment of invasive Gram-positive bacterial infections at Children's Medical Center Dallas from December 2003 to March 2007. Bacterial isolates were tested for susceptibility to daptomycin and characterized by pulsed-field gel electrophoresis and polymerase chain reaction for staphylococcal cassette chromosome mec A. Sixteen children (10 male; median age, 6.5 years) received daptomycin. Fifteen (94%) children had invasive staphylococcal disease (14, MRSA, of which 13 were community-associated; 1, methicillin-susceptible S. aureus), and 1 had urinary tract infection caused by VRE. Twelve children with disseminated staphylococcal disease had bacteremia for 2-10 days despite therapy with 2 or more of the following: vancomycin, clindamycin, rifampin, aminoglycoside, or linezolid. The addition of daptomycin resulted in bacteriologic cure in 6 of 7 evaluable patients with persistent bacteremia. No adverse events were attributed to daptomycin. Overall, 14 patients improved and were discharged home, and 2 died of complications of their underlying medical conditions. The majority of patients demonstrated clinical improvement after addition of daptomycin to conventional antimicrobial therapy. Further studies are needed to assess the pharmacokinetics, pharmacodynamics, safety, and effectiveness of daptomycin in infants and children.

Structure—Antibacterial Activity of Arylcarbonyl‐ and Arylsulfonyl‐Piperazine 5‐Triazolylmethyl Oxazolidinones.

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Synthesis and antibacterial activity of novel oxazolidinones with methylene oxygen- and methylene sulfur-linked substituents at C5-position

Novel oxazolidinone derivatives of the lead compound RBx 8700, containing methylene oxygen- and methylene sulfur-linked substituents at the C5-position, were synthesized. Antibacterial screening of these compounds against a panel of resistant and susceptible Gram-positive and fastidious Gram-negative bacteria gave compounds 2 and 4 as new antibacterial agents.

Adenosine phosphonate inhibitors of lipid II: Alanyl tRNA ligase MurM from Streptococcus pneumoniae

Adenosine and 2′-deoxyadenosine phosphonate transition state analogues act as the first inhibitors for the MurMN/FemABX family of tRNA-dependent ligases implicated in high-level penicillin resistance in Gram-positive bacteria.

P1830 Susceptibility of Gram-positive pathogens to daptomycin and other antimicrobial agents: first results from the DAPTOGERM Surveillance Study

Revised Abstract Objectives: Drug resistance in Gram-positive bacteria has become an increasing problem over the past 20 years. New antibacterial agents such as the lipopeptide daptomycin (DAP), which was recently approved in the EU, have been developed to address this problem. Shortly after the approval, a surveillance study was started by a network of clinical microbiology laboratories to monitor the susceptibility of Gram-positive pathogens to DAP in Germany. This report comprises the results of isolates of five frequently encountered Gram-positive species collected in 49 laboratories from March to June 2006. Methods: A total of 1,520 isolates including oxacillin-susceptible Staphylococcus aureus (MSSA, n=360), oxacillin-resistant S. aureus (MRSA, n=286), Staphylococcus epidermidis (Se, n=262), Enterococcus faecalis (Es, n=209), Enterococcus faecium (Em, n=208), and Streptococcus pyogenes (Sp, n=195) were tested against DAP, linezolid (LZD), vancomycin (VAN) and other drugs. First isolates obtained from hospitalized patients with skin and soft tissue infections, respiratory tract infections, foreign body/catheter infections, or sepsis were included. MICs were determined in a central laboratory using the broth microdilution procedure according to the standard of the German DIN (Deutsches Institut fur Normung) 58940 guidelines. MICs of DAP were interpreted by the EUCAST criteria. Results: The majority of isolates was recovered from wound swabs (57.7%), blood samples (21.9%) and respiratory tract specimens (8.2%). MIC50/90 values of DAP for MSSA, MRSA, and Se each were 0.5/1 mg/L. All strains were inhibited by DAP at the EUCAST breakpoint of ≤1 mg/L. LZD and VAN were also active against all staphylococci. However, based on MIC50/90 values, DAP was up to 4fold more active than LZD or VAN. Of the Em isolates, 23 (11.1%) were resistant to VAN. In contrast, none of the Es isolates exhibited resistance to VAN. DAP inhibited all strains at 4 mg/L. MIC50/90 values of DAP for either enterococcal species were 2/4 mg/L. One Es strain was resistant to LZD (MIC 32 mg/L). DAP was more active than LZD or VAN against Sp. MIC50/90 values were 0.125/0.25 for DAP compared to 0.25/0.5 and 1/1 for VAN and LZD, respectively. The highest MICs of DAP for Sp isolates were 0.5 mg/L. Conclusion: DAP demonstrated excellent in vitro activity against frequently encountered Gram-positive species including multi-resistant isolates such as MRSA and VRE. Resistant strains were not detected.

P699 Antimicrobial effects of non-antibiotics on resistant Gram-positive bacteria

P699 Antimicrobial effects of non-antibiotics on resistant Gram-positive bacteria

Ceftobiprole – a case study

Ceftobiprole medocaril is a cephalosporin prodrug that is under investigation for treatment of complicated skin and skin-structure infections (cSSSIs) due to methicillin-resistant Staphylococcus aureus (MRSA) and hospital-acquired pneumonia (HAP), including ventilator-associated pneumonia due to suspected or proven MRSA. Ceftobiprole was designed to bind the penicillin-resistant targets in Gram-positive bacteria, resulting in potent bactericidal activity against methicillin-resistant MRSA and penicillin-resistant Streptococcus pneumoniae (PRSP). In microbiological studies, ceftobiprole has demonstrated a broad-spectrum profile, with activity against many Gram-positive bacteria and a variety of important pathogenic Gram-negative bacteria. Ceftobiprole medocaril is being studied in Phase III clinical trials for cSSSI, HAP and hospitalised community-acquired pneumonia (hCAP). Top-line Phase III results in the first cSSSI study (STRAUSS 1) showed a high cure rate and good tolerability. The second cSSSI trial (STRAUSS 2) is targeting infections caused by Gram-positive and Gram-negative bacteria, and includes patients with diabetic foot infections. Ceftobiprole is expected to combine the well-established advantages of the cephalosporin antibiotic class with an enhanced spectrum of action, including against resistant Gram-positive bacteria.

The Border Sequence of the Balhimycin Biosynthesis Gene Cluster from Amycolatopsis balhimycina Contains bbr, Encoding a StrR-Like Pathway-Specific Regulator

Balhimycin, produced by the actinomycete Amycolatopsis balhimycina DSM5908, is a glycopeptide antibiotic highly similar to vancomycin, the antibiotic of ‘last resort’ used for the treatment of resistant Gram-positive pathogenic bacteria. Partial sequence of the balhimycin biosynthesis gene cluster was previously reported. In this work, cosmids which overlap the region of the characterized gene cluster were isolated and sequenced. At the ‘left’ end of the cluster, genes were identified which are involved in balhimycin biosynthesis, transport, resistance and regulation. The ‘right’ end border is defined by a putative 3-deoxy-D-arabino-heptulosonate 7-phosphate synthase (dahp) gene. The proximate gene is similar to a type I polyketide synthase gene of the rifamycin producer Amycolatopsis mediterranei indicating that another biosynthesis gene cluster might be located directly next to the balhimycin gene cluster. The newly identified StrR-like pathway-specific regulator, Bbr, was characterized to be a DNA-binding protein and may have a role in balhimycin biosynthesis. Purified N-terminally His-tagged Bbr shows specific DNA-binding to five promoter regions within the gene cluster. By in silico analysis and by comparison of the DNA sequences binding Bbr, conserved inverted repeat sequences for the Bbr-binding site are proposed. The putative Bbr consensus sequence differs from that published for StrR.

Risk of Serotonin Syndrome with Concomitant Administration of Linezolid and Serotonin Agonists

Linezolid, an antimicrobial used to treat resistant gram-positive bacteria, can inhibit monoamine oxidase, an enzyme that metabolizes serotonin and other biogenic amines. Inhibition of this enzyme can predispose patients who are concomitantly taking serotonin agonists to serotonin syndrome. Because of the potential of linezolid to inhibit monoamine oxidase, premarketing studies were conducted with drugs such as selective serotonin reuptake inhibitors. No cases of serotonin syndrome were recorded. After linezolid was released to the United States market, several case reports of serotonin syndrome emerged. A literature search revealed 13 cases of serotonin syndrome occurring with the concomitant use of linezolid and drugs possessing serotonergic properties. To direct clinical management of this potential drug interaction, we reviewed reports of serotonin syndrome to determine relevant drug interactions with linezolid and serotonergic drugs and to characterize similarities and differences in the reported cases. Clinicians should obtain complete drug histories to identify patients at risk, strictly monitor drug therapy including concomitant drugs, and receive education about this potential drug interaction and the symptoms of serotonin syndrome.

Structure–antibacterial activity of arylcarbonyl- and arylsulfonyl-piperazine 5-triazolylmethyl oxazolidinones

A series of novel arylcarbonyl- and arylsulfonyl-piperazinyl 5-triazolylmethyl oxazolidinones were synthesized and tested against a panel of Gram-positive and Gram-negative bacterial clinical isolates. The arylcarbonyl oxazolidinone derivatives showed strong in vitro antibacterial activity against susceptible and resistant Gram-positive pathogenic bacteria and were more active than the arylsufonyl derivatives. Substitution of varied electron-withdrawing and electron-donating groups on the phenyl ring in the arylcarbonyl series did not alter antibacterial activity significantly. However, in the arylsufonyl series, methyl substitution on the phenyl ring resulted in the loss of antibacterial activity. Antibacterial activity could not be directly correlated with the calculated partition coefficient (Clog P) values in this series of compounds.

Use of linear, Weibull, and log-logistic functions to model pressure inactivation of seven foodborne pathogens in milk

Survival curves of six foodborne pathogens suspended in ultra high-temperature (UHT) whole milk and exposed to high hydrostatic pressure at 21.5 °C were obtained. Vibrio parahaemolyticus was treated at 300 MPa and other pathogens, Listeria monocytogenes, Escherichia coli O157:H7, Salmonella enterica serovar Enteritidis, Salmonella enterica serovar Typhimurium, and Staphylococcus aureus were treated at 600 MPa. All the survival curves showed a rapid initial drop in bacterial counts followed by tailing caused by a diminishing inactivation rate. A linear model and two nonlinear models were fitted to these data and the performances of these models were compared using mean square error (MSE) values. The log-logistic and Weibull models consistently produced better fits to the inactivation data than the linear model. The mean MSE value of the linear model was 6.1, while the mean MSE values were 0.7 for the Weibull model and 0.3 for the log-logistic model. There was no correlation between pressure resistance and the taxonomic group the bacteria belong to. The order, most to least pressure-sensitive, of the single strains tested was: V. parahaemolyticus (gram negative)< L. monocytogenes (gram positive)< Salmonella Typhimurium (gram negative) ≅ Salmonella Enteritidis (gram negative)< E. coli O157:H7≅ Staphylocollus aureus (gram positive)< Shigella flexneri (gram negative). The most pressure-resistant gram-negative bacterium, Shigella flexneri, and most pressure resistant gram-positive bacterium, Staphylocollus aureus, were pressurized at 50 °C. Staphylocollus aureus was treated at 500 MPa and Shigella flexneri at 600 MPa. Elevated temperature considerably enhanced pressure inactivation of these two pathogens, but did not affect the overall shape of the survival curves. Pressure level (250 MPa) and substrate (1% peptone water plus 3% NaCl) in which V. parahaemolyticus was suspended affected the shape of survival curves of V. parahaemolyticus.

Antibacterial activity of pyrrolopyridine-substituted oxazolidinones: synthesis and in vitro SAR of various C-5 acetamide replacements

A series of pyrrolopyridine-substituted oxazolidinones containing various C-5 acetamide isosteres was synthesized and the structure–antibacterial activity relationships determined against a representative panel of susceptible and resistant Gram-positive bacteria.