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2.  Current Concepts in Antimicrobial Therapy Against Select Gram-Positive Organisms: Methicillin-Resistant Staphylococcus aureus, Penicillin-Resistant Pneumococci, and Vancomycin-Resistant Enterococci 
Mayo Clinic Proceedings  2011;86(12):1230-1243.
Gram-positive bacteria cause a broad spectrum of disease in immunocompetent and immunocompromised hosts. Despite increasing knowledge about resistance transmission patterns and new antibiotics, these organisms continue to cause significant morbidity and mortality, especially in the health care setting. Methicillin-resistant Staphylococcus aureus poses major problems worldwide as a cause of nosocomial infection and has emerged as a cause of community-acquired infections. This change in epidemiology affects choices of empirical antibiotics for skin and skin-structure infections and community-acquired pneumonia in many settings. Throughout the world, the treatment of community-acquired pneumonia and other respiratory tract infections caused by penicillin-resistant Streptococcus pneumoniae has been complicated by resistance to β-lactam and macrolide antibacterial drugs. Vancomycin-resistant enterococci are a major cause of infection in the hospital setting and remain resistant to treatment with most standard antibiotics. Treatment of diseases caused by resistant gram-positive bacteria requires appropriate use of available antibiotics and stewardship to prolong their effectiveness. In addition, appropriate and aggressive infection control efforts are vital to help prevent the spread of resistant pathogens.
PMCID: PMC3228624  PMID: 22134942
3.  10 × '20 Progress—Development of New Drugs Active Against Gram-Negative Bacilli: An Update From the Infectious Diseases Society of America 
Infections caused by antibiotic-resistant bacteria, especially the “ESKAPE” pathogens, continue to increase in frequency and cause significant morbidity and mortality. New antimicrobial agents are greatly needed to treat infections caused by gram-negative bacilli (GNB) resistant to currently available agents. The Infectious Diseases Society of America (IDSA) continues to propose legislative, regulatory, and funding solutions to this continuing crisis. The current report updates the status of development and approval of systemic antibiotics in the United States as of early 2013. Only 2 new antibiotics have been approved since IDSA's 2009 pipeline status report, and the number of new antibiotics annually approved for marketing in the United States continues to decline. We identified 7 drugs in clinical development for treatment of infections caused by resistant GNB. None of these agents was included in our 2009 list of antibacterial compounds in phase 2 or later development, but unfortunately none addresses the entire spectrum of clinically relevant GNB resistance. Our survey demonstrates some progress in development of new antibacterial drugs that target infections caused by resistant GNB, but progress remains alarmingly elusive. IDSA stresses our conviction that the antibiotic pipeline problem can be solved by the collaboration of global leaders to develop creative incentives that will stimulate new antibacterial research and development. Our aim is the creation of a sustainable global antibacterial drug research and development enterprise with the power in the short term to develop 10 new, safe, and efficacious systemically administered antibiotics by 2020 as called for in IDSA's “10 × '20 Initiative.”
PMCID: PMC3707426  PMID: 23599308
antibacterial agents; antimicrobials; gram-negative bacilli; drug development; clinical trials; antibiotic pipeline
4.  Design of clinical trials of antibacterial agents for community-acquired bacterial pneumonia 
Clinical investigation  2011;1(1):19-32.
Standards for the conduct of clinical trials of antibacterial agents for community-acquired bacterial pneumonia (CABP) have changed dramatically in recent years. A draft guidance from the US FDA on the conduct of such trials was issued in March 2009. However, the guidance has already faced substantial criticism during the open public comment period, resulting in uncertainty regarding the appropriate design of such studies from a regulatory perspective. Controversies regarding the magnitude of the treatment effect associated with antibacterial therapy versus placebo/no therapy, the appropriate timing, nature and noninferiority margin for the primary efficacy end point, and other clinical and statistical issues have complicated efforts to reach consensus on appropriate trial design of antibacterial therapy for CABP. It is critical that studies of new drugs for CABP are designed to ensure that they are feasible to conduct and that their results are scientifically valid, statistically rigorous and clinically meaningful. Based on 3 years of active dialog between clinical, statistical, and regulatory experts, this article proposes an approach to enable a balance of clinical trial feasibility with appropriate scientific, statistical and clinical rigor.
PMCID: PMC3173946  PMID: 21927712
clinical trial; community-acquired bacterial pneumonia; composite end point; justification of noninferiority margin; noninferiority study
5.  Antimicrobial Agents for Complicated Skin and Skin-Structure Infections: Justification of Noninferiority Margins in the Absence of Placebo-Controlled Trials 
The United States Food and Drug Administration requires clinical trial noninferiority margins to preserve a fraction (eg, 50%) of the established comparator drug's efficacy versus placebo. Lack of placebo-controlled trials for many infections complicates noninferiority margin justification for and, hence, regulatory review of new antimicrobial agents. Noninferiority margin clarification is critical to enable new antimicrobial development. In the absence of placebo-controlled trials, we sought to define the magnitude of efficacy of antimicrobial agents and resulting noninferiority margins for studies of complicated skin and skin-structure infection (SSSI).
We systematically reviewed literature on complicated SSSI published during 1900–1950 (before widespread penicillin resistance) to define treatment outcomes and confidence intervals (CIs). Antimicrobial efficacy was calculated as the lower limit CI of the cure rate with antimicrobials minus the upper limit CI of the cure rate without antimicrobials.
We identified 90 articles describing >28,000 patients with complicated SSSI. For cellulitis/erysipelas, cure rates were 66% (95% CI, 64%–68%) without antibiotics and 98% (95% CI, 96%–99%) for penicillin-treated patients, and penicillin reduced mortality by 10%. Cure rates for wound/ulcer infections were 36% (95% CI, 32%–39%) without antibiotics and 83% (95% CI, 81%–85%) for penicillin-treated patients. For major abscesses, cure rates were 76% (95% CI, 71%–80%) without antibiotics and 96% (95% CI, 94%–98%) for penicillin-treated patients; penicillin reduced mortality by 6%.
Systematic review of historical literature enables rational noninferiority margin justification in the absence of placebo-controlled trials and may facilitate regulatory review of noninferiority trials. Noninferiority margins of 14% for cellulitis/erysipelas, 21% for wound/ulcer infections, and 7% for major abscesses would preserve ≥50% of antibiotic efficacy versus placebo for these complicated SSSI subsets.
PMCID: PMC2808402  PMID: 19555285
6.  Community-based outpatient parenteral antimicrobial therapy (CoPAT) for Staphylococcus aureus bacteraemia with or without infective endocarditis: analysis of the randomized trial comparing daptomycin with standard therapy 
Administering outpatient parenteral antimicrobial therapy in the community setting (CoPAT) is becoming more common with the increasing emphasis on controlling costs. However, few controlled trials have evaluated this treatment modality.
Using data from a recent randomized trial comparing daptomycin with standard therapy (semi-synthetic penicillin or vancomycin, each with initial low-dose gentamicin) for Staphylococcus aureus bacteraemia and infective endocarditis (SAB/IE), patient characteristics and outcomes were evaluated. Patients receiving their full course of therapy in the hospital setting were compared with those who received some portion outside of the hospital (CoPAT).
Among the 200 patients, 51.5% received CoPAT. These patients were generally younger (median age 50 versus 54 years, P = 0.028). In the CoPAT group, there tended to be fewer patients with endocardial involvement (8.7% versus 18.6%, P = 0.061) and pre-existing valvular heart disease (7.8% versus 15.5%, P = 0.120). CoPAT patients received longer therapy courses (mean 25.4 versus 13.5 days, P < 0.001) and had higher rates of therapy completion (90.3% versus 45.4%, P < 0.001) and clinical success (86.4% versus 55.7%, P < 0.001). Persisting or relapsing S. aureus was less frequent in the CoPAT group (3.9% versus 15.5%, P = 0.007) and there were fewer deaths (3.9% versus 18.6%, P = 0.001) 6 weeks after the end of therapy. Hospital readmission occurred for 18 of the 103 (17.5%) CoPAT patients. Clinical success rates were similar for CoPAT patients receiving daptomycin (90.0%) or standard therapy (83.0%).
With proper monitoring, stable patients can complete treatment for SAB/IE as outpatients in the community setting. Daptomycin is an appropriate option for this setting.
PMCID: PMC2667135  PMID: 19264792
outcomes; hospital readmission; OPAT; vancomycin; semi-synthetic penicillin
7.  Associations between the Genotypes of Staphylococcus aureus Bloodstream Isolates and Clinical Characteristics and Outcomes of Bacteremic Patients ▿  
Journal of Clinical Microbiology  2008;46(9):2890-2896.
We investigated associations between the genotypic and phenotypic features of Staphylococcus aureus bloodstream isolates and the clinical characteristics of bacteremic patients enrolled in a phase III trial of S. aureus bacteremia and endocarditis. Isolates underwent pulsed-field gel electrophoresis, PCR for 33 putative virulence genes, and screening for heteroresistant glycopeptide intermediate S. aureus (hGISA). A total of 230 isolates (141 methicillin-susceptible S. aureus and 89 methicillin-resistant S. aureus [MRSA]) were analyzed. North American and European S. aureus isolates differed in their genotypic characteristics. Overall, 26% of the MRSA bloodstream isolates were USA 300 strains. Patients with USA 300 MRSA bacteremia were more likely to be injection drug users (61% versus 15%; P < 0.001), to have right-sided endocarditis (39% versus 9%; P = 0.002), and to be cured of right-sided endocarditis (100% versus 33%; P = 0.01) than patients with non-USA 300 MRSA bacteremia. Patients with persistent bacteremia were less likely to be infected with Panton-Valentine leukocidin gene (pvl)-constitutive MRSA (19% versus 56%; P = 0.005). Although 7 of 89 MRSA isolates (8%) exhibited the hGISA phenotype, no association with persistent bacteremia, daptomycin resistance, or bacterial genotype was observed. This study suggests that the virulence gene profiles of S. aureus bloodstream isolates from North America and Europe differ significantly. In this study of bloodstream isolates collected as part of a multinational randomized clinical trial, USA 300 and pvl-constitutive MRSA strains were associated with better clinical outcomes.
PMCID: PMC2546778  PMID: 18596141
8.  In Vivo Activity of Evernimicin (SCH 27899) against Methicillin-Resistant Staphylococcus aureus in Experimental Infective Endocarditis 
Currently, there exist few satisfactory alternatives to vancomycin for therapy of serious methicillin-resistant Staphylococcus aureus (MRSA) infections. We employed a rat model of aortic valve endocarditis to assess the potential efficacy of evernimicin (SCH 27899) compared with vancomycin against infection with a strain susceptible to both agents (MICs of 0.25 and 0.50 μg/ml, respectively). Infected animals were assigned to one of three groups: controls (no treatment), evernimicin at 60 mg/kg of body weight by intravenous (i.v.) infusion once daily, or vancomycin at 150 mg/kg of body weight per day by continuous i.v. infusion. Therapy was administered for 5.5 days. At the start of therapy, colony counts in vegetations were 6.63 ± 0.44 log10 CFU/g. In both treatment groups, bacterial density within vegetations was significantly reduced in comparison with control animals that had not been treated. Final colony counts were as follows (mean ± standard deviation): controls, 10.12 ± 1.51 log10 CFU/g of vegetation; evernimicin, 7.22 ± 2.91 log10 CFU/g of vegetation; vancomycin, 5.65 ± 1.76 log10 CFU/g of vegetation. The difference between the evernimicin and vancomycin groups was not significant. These results confirmed the bacteriostatic activity of evernimicin in vivo in an experimental model of severe MRSA infection.
PMCID: PMC90262  PMID: 11120967
9.  In Vitro Activities of the Glycylcycline GAR-936 against Gram-Positive Bacteria 
The in vitro activities of GAR-936, the 9-t-butylglycylamido derivative of minocycline, were compared with those of doxycycline, minocycline, and tetracycline against 527 gram-positive clinical isolates. GAR-936 inhibited all strains, including those resistant to other tetracyclines, at concentrations of ≤2 μg/ml, except two strains of JK diphtheroids for which the MIC was 4 μg/ml.
PMCID: PMC90048  PMID: 10898710

Results 1-9 (9)