Publications by authors named "Ribhi Shawar"

14 Publications

  • Page 1 of 1

FDA-CDC Antimicrobial Resistance Isolate Bank: a Publicly Available Resource To Support Research, Development, and Regulatory Requirements.

J Clin Microbiol 2018 02 24;56(2). Epub 2018 Jan 24.

Division of Healthcare Quality Promotion, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.

The FDA-CDC Antimicrobial Resistance Isolate Bank was created in July 2015 as a publicly available resource to combat antimicrobial resistance. It is a curated repository of bacterial isolates with an assortment of clinically important resistance mechanisms that have been phenotypically and genotypically characterized. In the first 2 years of operation, the bank offered 14 panels comprising 496 unique isolates and had filled 486 orders from 394 institutions throughout the United States. New panels are being added.
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http://dx.doi.org/10.1128/JCM.01415-17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5786719PMC
February 2018

Topical retapamulin in the management of infected traumatic skin lesions.

Ther Clin Risk Manag 2009 Feb 26;5(1):41-9. Epub 2009 Mar 26.

Infectious Disease Center for Excellence in Drug Discovery, GlaxoSmithKline, Collegeville, PA, USA;

Retapamulin is a novel semisynthetic pleuromutilin antibiotic specifically designed for use as a topical agent. The unique mode of action by which retapamulin selectively inhibits bacterial protein synthesis differentiates it from other nonpleuromutilin antibacterial agents that target the ribosome or ribosomal factors, minimizing the potential for target-specific cross-resistance with other antibacterial classes in current use. In vitro studies show that retapamulin has high potency against the Gram-positive bacteria (Staphylococcus aureus, Streptococcus pyogenes, and coagulase-negative staphylococci) commonly found in skin and skin-structure infections (SSSIs), including S. aureus strains with resistance to agents such as macrolides, fusidic acid, or mupirocin, and other less common organisms associated with SSSIs, anaerobes, and common respiratory tract pathogens. Clinical studies have shown that twice-daily topical retapamulin for 5 days is comparable to 10 days of oral cephalexin in the treatment of secondarily infected traumatic lesions. A 1% concentration of retapamulin ointment has been approved for clinical use as an easily applied treatment with a short, convenient dosing regimen for impetigo. Given the novel mode of action, low potential for cross-resistance with established antibacterial agents, and high in vitro potency against many bacterial pathogens commonly recovered from SSSIs, retapamulin is a valuable enhancement over existing therapeutic options.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2697516PMC
http://dx.doi.org/10.2147/tcrm.s3459DOI Listing
February 2009

Microbiological profile of a new topical antibacterial: retapamulin ointment 1%.

Expert Rev Anti Infect Ther 2009 Apr;7(3):269-79

GlaxoSmithKline, Collegeville, PA 19426, USA.

Retapamulin is a new topical pleuromutilin antibiotic for the treatment of skin and skin-structure infections, including impetigo. In vitro studies indicate that retapamulin has a unique mode of action that minimizes the potential for target-specific cross-resistance with other antibacterials and a limited potential for resistance development. Its spectrum of activity includes the most likely causative pathogens Staphylococcus aureus and Streptococcus pyogenes. In the Global Surveillance Program, retapamulin was highly active in vitro, including against strains of S. aureus resistant to methicillin, mupirocin or fusidic acid. In clinical studies, retapamulin was noninferior to fusidic acid and oral cefalexin, achieving per-pathogen success rates of 86-99%. Topical retapamulin has a good safety profile and is associated with high patient compliance.
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http://dx.doi.org/10.1586/eri.09.7DOI Listing
April 2009

Genetic characterization of Vga ABC proteins conferring reduced susceptibility to pleuromutilins in Staphylococcus aureus.

Antimicrob Agents Chemother 2008 Dec 6;52(12):4507-9. Epub 2008 Oct 6.

Department of Microbiology, ID-CEDD, GlaxoSmithKline, Collegeville, Pennsylvania 19426, USA.

Retapamulin MICs of > or =2 microg/ml were noted for 6 of 5,676 S. aureus recent clinical isolates evaluated. The ABC proteins VgaAv and VgaA were found to be responsible for the reduced susceptibility to pleuromutilins exhibited by these six isolates.
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http://dx.doi.org/10.1128/AAC.00915-08DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2592886PMC
December 2008

Molecular epidemiology of methicillin-resistant and methicillin-susceptible Staphylococcus aureus isolates from global clinical trials.

J Clin Microbiol 2008 Sep 9;46(9):2842-7. Epub 2008 Jul 9.

Department of Medical Microbiology and Immunology, Creighton University School of Medicine, Omaha, NE 68178, USA.

Determining the genetic characteristics of Staphylococcus aureus is important for better understanding of the global and dynamic epidemiology of this organism as we witness the emergence and spread of virulent and antibiotic-resistant clones. We genotyped 292 S. aureus isolates (105 methicillin resistant and 187 methicillin susceptible) using a combination of pulsed-field gel electrophoresis, multilocus sequence typing, and SCCmec typing. In addition, S. aureus isolates were tested for the presence of the Panton-Valentine leukocidin (PVL) genes. Isolates were recovered from patients with uncomplicated skin infections in 10 different countries during five phase III global clinical trials of retapamulin, a new topical antibiotic agent. The most common methicillin-resistant clone had multilocus sequence type 8, pulsed-field type USA300, and SCCmec type IV and possessed the PVL genes. This clone was isolated exclusively in the United States. The most common PVL-positive, methicillin-susceptible clone had multilocus sequence type 121 and pulsed-field type USA1200. This clone was found primarily in South Africa and the Russian Federation. Other clones were found at lower frequencies and were limited in their geographic distribution. Overall, considerable genetic diversity was observed within multilocus sequence type clonal complexes and pulsed-field types.
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http://dx.doi.org/10.1128/JCM.00521-08DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2546764PMC
September 2008

A geographic variant of the Staphylococcus aureus Panton-Valentine leukocidin toxin and the origin of community-associated methicillin-resistant S. aureus USA300.

J Infect Dis 2008 Jan;197(2):187-94

Evolutionary and Structural Bioinformatics, Collegeville, Pennsylvania, USA.

Background: The majority of recent community-associated methicillin-resistant Staphylococcus aureus (MRSA) infections in the United States have been caused by a single clone, USA300. USA300 secretes Panton-Valentine leukocidin (PVL) toxin, which is associated with highly virulent infections.

Methods: We sequenced the PVL genes of 174 S. aureus isolates from a global clinical sample. We combined phylogenetic reconstruction and protein modeling methods to analyze genetic variation in PVL.

Results: Nucleotide variation was detected at 12 of 1726 sites. Two PVL sequence variants, the R variant and the H variant, were identified on the basis of a substitution at nt 527. Of sequences obtained in the United States, 96.7% harbor the R variant, whereas 95.6% of sequences obtained outside the United States harbor the H variant; 91.3% of MRSA isolates harbor the R variant, and 91.3% of methicillin-susceptible strains harbor the H variant. A molecular model of PVL shows 3 mechanisms by which the amino acid substitution may affect PVL function.

Conclusions: All sampled PVL genes appear to share a recent common ancestor and spread via a combination of clonal expansion and horizontal transfer. US isolates harbor a variant of PVL that is strongly associated with MRSA infections. Protein modeling reveals that this variant may have functional significance. We propose a hypothesis for the origin of USA300.
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http://dx.doi.org/10.1086/524684DOI Listing
January 2008

Topical retapamulin ointment, 1%, versus sodium fusidate ointment, 2%, for impetigo: a randomized, observer-blinded, noninferiority study.

Dermatology 2007 ;215(4):331-40

Department of Dermatology and Venereology (Pediatric Dermatology), University Medical Center/Sophia Children's Hospital, Rotterdam, The Netherlands.

Background: Retapamulin is a novel pleuromutilin antibacterial developed for topical use.

Objective: To compare the efficacy and safety of retapamulin ointment, 1% (twice daily for 5 days), with sodium fusidate ointment, 2% (3 times daily for 7 days), in impetigo.

Methods: A randomized (2:1 retapamulin to sodium fusidate), observer-blinded, noninferiority, phase III study in 519 adult and pediatric (aged > or = 9 months) subjects.

Results: Retapamulin and sodium fusidate had comparable clinical efficacies (per-protocol population: 99.1 and 94.0%, respectively; difference: 5.1%, 95% confidence interval: 1.1-9.0%, p = 0.003; intent-to-treat population: 94.8 and 90.1%, respectively; difference: 4.7%, 95% confidence interval: -0.4 to 9.7%, p = 0.062). Bacteriological efficacies were similar. Success rates in the small numbers of sodium-fusidate-, methicillin- and mupirocin-resistant Staphylococcus aureus were good for retapamulin (9/9, 8/8 and 6/6, respectively). Both drugs were well tolerated.

Conclusion: Retapamulin is a highly effective and convenient new treatment option for impetigo, with efficacy against isolates resistant to existing therapies.
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http://dx.doi.org/10.1159/000107776DOI Listing
October 2007

Topical retapamulin ointment (1%, wt/wt) twice daily for 5 days versus oral cephalexin twice daily for 10 days in the treatment of secondarily infected dermatitis: results of a randomized controlled trial.

J Am Acad Dermatol 2006 Dec 6;55(6):1003-13. Epub 2006 Oct 6.

Department of Dermatology and Cutaneous Biology, Jefferson Medical College of Thomas Jefferson University, Philadelphia, Pennsylvania, USA.

Background: New antibacterial agents with activity against pathogenic strains resistant to established antibiotics are needed to treat patients with secondarily infected dermatitis (SID).

Objective: We sought to determine the clinical safety and efficacy of topical retapamulin ointment 1% versus oral cephalexin for the treatment of SID.

Methods: Patients with SID were randomly assigned to retapamulin ointment 1% (twice daily [bid]) for 5 days, or oral cephalexin (500 mg bid) for 10 days. The primary efficacy end point was clinical response at follow-up. Secondary outcomes included microbiologic response at follow-up, safety, and compliance.

Results: Retapamulin was as effective as cephalexin (clinical success rates at follow-up: 85.9% and 89.7%, respectively). Microbiologic success rates at follow-up were 87.2% for retapamulin and 91.8% for cephalexin. Retapamulin was well tolerated and the topical formulation was preferred over the oral drug.

Limitations: An imbalance existed in the number of patients with the clinical outcome "unable to determine" (15 retapamulin, 2 cephalexin), mainly because of their failure to attend the study visit. If those who failed to attend visits (who did not withdraw as a result of drug-related events) are removed from the analysis, the clinical success rates are 89.9% for retapamulin and 89.7% for cephalexin.

Conclusions: Retapamulin ointment 1% (bid) for 5 days was as effective as oral cephalexin (bid) for 10 days in treatment of patients with SID, and was well tolerated.
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http://dx.doi.org/10.1016/j.jaad.2006.08.058DOI Listing
December 2006

Retapamulin ointment twice daily for 5 days vs oral cephalexin twice daily for 10 days for empiric treatment of secondarily infected traumatic lesions of the skin.

Skinmed 2006 Sep-Oct;5(5):224-32

Anniston Medical Clinic/Pinnacle Research Group, Anniston, AL, USA.

Introduction: Retapamulin is a novel, topical antibacterial of the pleuromutilin class in development for the treatment of secondarily infected traumatic lesions of the skin.

Methods: The efficacy, safety, and tolerability of topical retapamulin ointment, 1% for 5 days twice daily was evaluated in 2 identical, randomized, double-blind, double-dummy, multicenter studies vs oral cephalexin, 500 mg twice daily for 10 days, in 1904 patients with secondarily infected traumatic lesions.

Results: Clinical success rates were 89.5% in protocol-adherent patients receiving retapamulin compared with 91.9% for cephalexin (treatment difference, -2.5% [95% confidence interval, -5.4% to 0.5%]). In patients with Staphylococcus aureus or Streptococcus pyogenes at baseline, clinical success was 89.2% (365/409) for retapamulin and 92.6% (63/68) for cephalexin. Safety and tolerability were similar between treatments. Noncompliance (defined as using or taking <80% of doses) was recorded in 8.0% (51/636) of patients taking cephalexin compared with 0.39% (5/1268) of patients receiving retapamulin.

Conclusions: Retapamulin offers a novel, effective, and convenient topical treatment for secondarily infected traumatic lesions.
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http://dx.doi.org/10.1111/j.1540-9740.2006.05774.xDOI Listing
November 2006

Synthesis and antibacterial activity of C12 des-methyl ketolides.

Bioorg Med Chem Lett 2006 Sep 19;16(17):4692-6. Epub 2006 Jun 19.

Small Molecule Drug Discovery, Biopharma Research, Chiron Corporation, Emeryville, CA 94608, USA.

Synthesis of C(12) des-methyl ketolide is developed featuring an intramolecular epoxide formation/elimination process to establish the C(12) stereocenter. These ketolides are potent against several key respiratory pathogens, including erythromycin resistant erm- and mef-containing strains of Streptococcus pneumoniae.
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http://dx.doi.org/10.1016/j.bmcl.2006.05.104DOI Listing
September 2006

Synthesis and antibacterial activity of novel C12 ethyl ketolides.

Bioorg Med Chem 2006 Aug 11;14(16):5592-604. Epub 2006 May 11.

Chiron Corporation, Biopharma Research, Emeryille, CA 94608-2916, USA.

A novel series of C(12) ethyl erythromycin derivatives have been discovered which exhibit in vitro and in vivo potency against key respiratory pathogens, including those resistant to erythromycin. The C(12) modification involves replacing the natural C(12) methyl group in the erythromycin core with an ethyl group via chemical synthesis. From the C(12) ethyl macrolide core, a series of C(12) ethyl ketolides were prepared and tested for antibacterial activity against a panel of relevant clinical isolates. Several compounds were found to be potent against macrolide-sensitive and -resistant bacteria, whether resistance was due to ribosome methylation (erm) or efflux (mef). In particular, the C(12) ethyl ketolides 4k,4s,4q,4m, and 4t showed a similar antimicrobial spectrum and comparable activity to the commercial ketolide telithromycin. The in vivo efficacy of several C(12) ethyl ketolides was demonstrated in a mouse infection model with Streptococcus pneumoniae as pathogen.
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http://dx.doi.org/10.1016/j.bmc.2006.04.032DOI Listing
August 2006

Synthesis and antibacterial activity of novel C12 vinyl ketolides.

J Med Chem 2006 Mar;49(5):1730-43

Chiron Corporation, Biopharma Research, 4560 Horton Street, Emeryille, California 94608-2916, USA.

A novel series of C12 vinyl erythromycin derivatives have been discovered which exhibit in vitro and in vivo potency against key respiratory pathogens. The C12 modification involves replacing the natural C12 methyl group in the erythromycin core with a vinyl group via chemical synthesis. From the C12 vinyl macrolide core, a series of C12 vinyl ketolides was prepared. Several compounds were found to be potent against macrolide-sensitive and -resistant bacteria. The C12 vinyl ketolides 6j and 6k showed a similar antimicrobial spectrum and comparable activity to the commercial ketolide telithromycin. However, the pharmacokinetic profiles of C12 vinyl ketolides 6j and 6k in rats differ from that of telithromycin by having higher lung-to-plasma ratios, larger volumes of distribution, and longer half-lives. These pharmacokinetic differences have a pharmacodynamic effect as both 6j and 6k exhibited better in vivo efficacy than telithromycin in rat lung infection models against Streptococcus pneumoniae and Haemophilus influenzae.
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http://dx.doi.org/10.1021/jm051157aDOI Listing
March 2006

A prodrug approach toward the development of water soluble fluoroquinolones and structure--activity relationships of quinoline-3-carboxylic acids.

J Med Chem 2004 Sep;47(19):4693-709

Chiron Corporation, 201 Elliott Avenue West, Seattle, Washington 98119, USA.

A fluoroquinolone prodrug, PA2808, was prepared and shown to convert to the highly active parent drug PA2789. In vitro and in vivo activation of PA2808 by alkaline phosphatase was demonstrated using disk diffusion and rat lung infection models. The water solubility of PA2808 showed a marked increase compared to PA2789 over a pH range suitable for aerosol drug delivery. A total of 48 analogues based on PA2789 were prepared and screened against a panel of Gram-positive and Gram-negative pathogens. Incorporating a cyclopropane-fused pyrrolidine (amine) at C-7 resulted in some of the most active analogues.
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http://dx.doi.org/10.1021/jm0497895DOI Listing
September 2004