Discovery and hit-to-lead evaluation of piperazine amides as selective, state-dependent NaV1.7 inhibitors.

NaV1.7 is a particularly compelling target for the treatment of pain. Herein, we report the discovery and evaluation of a series of piperazine amides that exhibit state-dependent inhibition of NaV1.7. After demonstrating significant pharmacodynamic activity with early lead compound 14 in a NaV1.7-dependent behavioural mouse model, we systematically established SAR trends throughout each sector of the scaffold. The information gleaned from this modular analysis was then applied additively to quickly access analogues that encompass an optimal balance of properties, including NaV1.7 potency, selectivity over NaV1.5, aqueous solubility, and microsomal stability.

Severity of illness scoring systems in patients with bacteraemic pneumococcal pneumonia: implications for the intensive care unit care.

Severity of illness scoring systems are useful for decisions on the management of patients with community-acquired pneumonia (CAP), including assessing the need for intensified therapy and monitoring, or for intensive care unit (ICU) admission. We compared the accuracy of the Pneumonia Severity Index (PSI), the CURB-65 and CRB-65 score, the modified-American Thoracic Society score (ATS), the IDSA/ATS guidelines and the Pitt Bacteraemia score (PBS) in evaluating severity of illness in 766 patients with bacteraemic pneumococcal pneumonia. We evaluated the sensitivity and specificity, the positive predictive value (PPV) and the negative predictive value (NPV) and the accuracy of the classification in predicting 14-day mortality. The PSI and the IDSA/ATS guidelines were the most sensitive whereas the PBS and modified-ATS scoring systems were the most specific in predicting mortality. The NPV was comparable for all four scoring systems (all above 90%), but the PPV was highest for PBS (54.2%) and lowest for PSI (23.2%). The predictive accuracy and discriminating power as measured by the receiver-operating characteristic (ROC) curve was highest for the PBS. Both the modified-ATS and the PBS scoring systems identified those patients who might benefit most from intensified care and monitoring. The PBS and modified-ATS proved superior to the IDSA/ATS guidelines, CURB-65 and CRB-65 with respect to their specificity and PPV. The low PPV of the PSI rendered it not usable as a parameter for decision-making in severely-ill patients with pneumococcal bacteraemia.

New antimicrobial agents as therapy for resistant gram-positive cocci.

Vancomycin- and methicillin-resistant gram-positive cocci have emerged as an increasingly problematic cause of hospital-acquired infections. We conducted a literature review of newer antibiotics with activity against vancomycin-resistant and methicillin-resistant gram-positive cocci. Quinupristin/dalfopristin, linezolid, daptomycin, and tigecycline have in vitro activity for methicillin-resistant staphylococci and are superior to vancomycin for vancomycin-resistant isolates. Dalbavancin, telavancin, and oritavancin are new glycopeptides that have superior pharmacodynamic properties compared to vancomycin. We review the antibacterial spectrum, clinical indications and contraindications, pharmacologic properties, and adverse events associated with each of these agents. Daptomycin has rapid bactericidal activity for Staphylococcus aureus and is approved for use in bacteremia and right-sided endocarditis. Linezolid is comparable to vancomycin in patients with methicillin-resistant S. aureus (MRSA) pneumonia and has pharmacoeconomic advantages given its oral formulation. Quinupristin/dalfopristin is the drug of choice for vancomycin-resistant Enterococcus faecium infections but has no activity against Enterococcus faecalis. Tigecycline has activity against both enterococcus species and MRSA; it is also active against Enterobacteriaceae and anaerobes which allows for use in intra-abdominal and diabetic foot infections. A review of numerous in vitro and animal model studies shows that interaction between these newer agents and other antistaphylococcal agents for S. aureus are usually indifferent (additive).

Association of serotypes of Streptococcus pneumoniae with disease severity and outcome in adults: an international study.

BACKGROUND: The introduction of conjugate pneumococcal vaccination for children has reduced the burden of invasive disease due to pneumococcal conjugate vaccine (PCV) types (i.e., serotypes 9V, 14, 6B, 18C, 23F, 19F, and 4) in adults. As nonvaccine serotypes become predominant causes of invasive disease among adults, it is necessary to evaluate the disease severity and mortality associated with infection due to nonvaccine serotypes, compared with PCV serotypes, in adults. METHODS: The association of pneumococcal serotype and host-related variables with disease severity and mortality was statistically examined (with multivariable analysis) in 796 prospectively enrolled, hospitalized adult patients with bacteremia due to Streptococcus pneumoniae. RESULTS: In multivariate analyses of risk in patients with invasive pneumococcal disease, older age (age, > or = 65 years; P = .004), underlying chronic disease (P = .025), immunosuppression (P = .035), and severity of disease (P < .001) were significantly associated with mortality; no association was found between nosocomial infection with invasive serotypes 1, 5, and 7 and mortality. The risk factors meningitis (P = .001), suppurative lung complications (P < or = .001), and preexisting lung disease (P = .051) were significantly associated with disease severity, independent of infecting serotype. No differences were seen in disease severity or associated mortality among patients infected with PCV serotypes, compared with patients infected with nonvaccine serotypes. CONCLUSIONS: Our data support the notion that host factors are more important than isolate serotype in determining the severity and outcome of invasive pneumococcal disease and that these outcomes are unlikely to change in association with nonvaccine serotype infection in the post-conjugate vaccine era.

Effect of flow regimes on the presence of Legionella within the biofilm of a model plumbing system.

AIMS: Stagnation is widely believed to predispose water systems to colonization by Legionella. A model plumbing system was constructed to determine the effect of flow regimes on the presence of Legionella within microbial biofilms. METHODS AND RESULTS: The plumbing model contained three parallel pipes where turbulent, laminar and stagnant flow regimes were established. Four sets of experiments were carried out with Reynolds number from 10,000 to 40,000 and from 355 to 2,000 in turbulent and laminar pipes, respectively. Legionella counts recovered from biofilm and planktonic water samples of the three sampling pipes were compared with to determine the effect of flow regime on the presence of Legionella. Significantly higher colony counts of Legionella were recovered from the biofilm of the pipe with turbulent flow compared with the pipe with laminar flow. The lowest counts were in the pipe with stagnant flow. CONCLUSIONS: We were unable to demonstrate that stagnant conditions promoted Legionella colonization. SIGNIFICANCE AND IMPACT OF THE STUDY: Plumbing modifications to remove areas of stagnation including deadlegs are widely recommended, but these modifications are tedious and expensive to perform. Controlled studies in large buildings are needed to validate this unproved hypothesis.

Legionella: macrolides or quinolones?

Following the first outbreaks of legionnaire's disease, erythromycin emerged as the treatment of choice without the foundation of rigorous clinical trials. The number of therapeutic failures with erythromycin, as well as the side-effects and drug interactions, led to the consideration of other drugs such as the new macrolides and quinolones for the treatment of legionnaire's disease in the 1990s. In this article, 19 studies in in-vitro intracellular models and seven animal studies that compared macrolides to quinolones were reviewed. Quinolones were found to have greater activity in intracellular models and improved efficacy in animal models compared with macrolides. No randomised trials comparing the clinical efficacy of the new macrolides and new quinolones have ever been performed. Three observational studies totalling 458 patients with legionnaire's disease have compared the clinical efficacy of macrolides (not including azithromycin) and quinolones (mainly levofloxacin). The results suggested that quinolones may produce a superior clinical response compared with the macrolides (erythromycin and clarithromycin) with regard to defervescence, complications, and length of hospital stay. Little data exist for direct comparison of quinolones and azithromycin.

Endocarditis and pericarditis complicating pneumococcal bacteraemia, with special reference to the adhesive abilities of pneumococci: results from a prospective study.

The incidence of pneumococcal cardiac infections is unknown and the pathogenicity of such complications is poorly understood. In a prospective, international, observational study, eight of 844 patients hospitalised with Streptococcus pneumoniae bacteraemia developed endocarditis (n = 5) or pericarditis (n = 3). The clinical and microbiological characteristics of these patients were compared with those of control patients. The corresponding incidence of pneumococcal endocarditis was c. 1-3/1 million inhabitants/year. There was no common pattern in the medical history of patients with an infectious cardiac complication. The severity of illness upon admission was comparable with that for patients without infectious cardiac complications, as was the 14-day mortality rate (25% and 17%, respectively). For encapsulated S. pneumoniae, no significant differences were found between patients with infectious cardiac complications and controls in adherence assays. However, non-encapsulated S. pneumoniae showed higher hydrophobicity and increased adherence to human epithelial cells.

Staphylococcus lugdunensis endocarditis--the hidden peril of coagulase-negative staphylococcus in blood cultures.

Reported here is a successfully treated case of native mitral valve endocarditis caused by Staphylococcus lugdunensis and a review of 47 similar cases reported in the English literature. In the literature review, perineal skin flora appeared to be the source of the organism in patients with endocarditis. Staphylococcus lugdunensis is generally susceptible in vitro to beta-lactam agents. If speciation is not performed, these bacteria might be mistaken for Staphylococcus epidermidis, a relatively avirulent bacterium that is a common contaminant of cultures. Prompt speciation can lead to earlier recognition of endocarditis and possibly enable earlier surgical intervention with improved outcome for this high-mortality infection. Multiple positive blood cultures yielding coagulase-negative staphylococci should be identified to the species level; endocarditis or another intravascular source of infection should be sought.

Infectious diseases journals on the World Wide Web: attractions and limitations.

Online infectious diseases (ID) journals are an increasingly common Web phenomenon. We performed a study of practices in this evolving area that make these sites more usable and useful from the perspective of ID physicians. The Web sites of 18 journals pertaining to general ID and infection control and hospital epidemiology were evaluated for a set of 24 Web interface characteristics and online features. Journals hosted by the High Wire Press (Antimicrobial Agents and Chemotherapy, Infection and Immunity, and the Journal of Antimicrobial Chemotherapy) and the University of Chicago Press (The Journal of Infectious Diseases and Clinical Infectious Diseases) best fulfilled our criteria. Electronic reference linking, archives, e-mail alerts, and links to external resources are some of the features of electronic journals that users in the ID specialty may find especially useful.

Legionnaires' disease: seek and ye shall find.

Legionella pneumophila is among the top three or four microbial causes of community-acquired pneumonia, yet is often misdiagnosed and inadequately treated. New laboratory tests should simplify the diagnosis. Also, contrary to common perception, the disease is usually spread via aspiration of water from contaminated hot water distribution systems, not from air conditioning systems. The treatment of choice has shifted from erythromycin to the newer macrolides and quinolones. Routine culturing of the hospital water supply is a requisite first step in preventing hospital-acquired Legionnaires' disease.

Outcome of cephalosporin treatment for serious infections due to apparently susceptible organisms producing extended-spectrum beta-lactamases: implications for the clinical microbiology laboratory.

Although extended-spectrum beta-lactamases (ESBLs) hydrolyze cephalosporin antibiotics, some ESBL-producing organisms are not resistant to all cephalosporins when tested in vitro. Some authors have suggested that screening klebsiellae or Escherichia coli for ESBL production is not clinically necessary, and when most recently surveyed the majority of American clinical microbiology laboratories did not make efforts to detect ESBLs. We performed a prospective, multinational study of Klebsiella pneumoniae bacteremia and identified 10 patients who were treated for ESBL-producing K. pneumoniae bacteremia with cephalosporins and whose infecting organisms were not resistant in vitro to the utilized cephalosporin. In addition, we reviewed 26 similar cases of severe infections which had previously been reported. Of these 36 patients, 4 had to be excluded from analysis. Of the remaining 32 patients, 100% (4 of 4) patients experienced clinical failure when MICs of the cephalosporin used for treatment were in the intermediate range and 54% (15 of 28) experienced failure when MICs of the cephalosporin used for treatment were in the susceptible range. Thus, it is clinically important to detect ESBL production by klebsiellae or E. coli even when cephalosporin MICs are in the susceptible range (

Legionnaires' disease and pneumonia. Beware the temptation to underestimate this "exotic" cause of infection.

Legionnaires' disease is an often overlooked but common cause of community-acquired pneumonia. The clinical presentation is nonspecific, although fever higher than 39 degrees C (102.2 degrees F), gastrointestinal symptoms, and hyponatremia should raise the index of suspicion. In this article, Drs Akbas and Yu describe specialized laboratory tests needed for definitive diagnosis and discuss therapeutic options.

The role of topical antibiotic prophylaxis in patients undergoing contaminated head and neck surgery with flap reconstruction.

OBJECTIVES/HYPOTHESIS: Patients undergoing contaminated head and neck surgery with flap reconstruction have wound infection rates of 20% to 25% with parenteral antibiotic prophylaxis. Studies suggest that perioperative antimicrobial mouthwash reduces oropharyngeal flora and may prevent wound infections. We hypothesized that the addition of topical antibiotics to a parenteral prophylactic regimen would reduce the incidence of wound infection in these high-risk patients. STUDY DESIGN: We performed a randomized, prospective clinical trial. METHODS: Patients received either 1) parenteral piperacillin/tazobactam (3.375 g every 6 hours for 48 h) or 2) parenteral piperacillin/tazobactam plus topical piperacillin/tazobactam administered as a mouthwash immediately before surgery and once a day for 2 days postoperatively, with piperacillin/tazobactam added to the intraoperative irrigation solution. The wounds of all patients were evaluated daily using predefined objective criteria. RESULTS: Sixty-two patients met inclusion criteria and were enrolled in the study. The overall wound infection rate was 8.1% (95% confidence interval [CI], 2.7%-17.8%). Two of 31 patients (6.4%) who received parenteral antibiotics alone developed a wound infection compared with 3 of 31 patients (9.7%) randomly assigned to receive topical plus parenteral antibiotics. This difference was not statistically significant (P = >.05). Infection rate was not associated with flap type (rotational vs. free tissue transfer), mandibular reconstruction, age, gender, tumor site, stage, surgical duration, or blood loss. CONCLUSIONS: These results suggest that piperacillin/tazobactam is a highly effective antibiotic for prevention of wound infection in patients undergoing flap reconstruction following contaminated head and neck surgery. However, the addition of topical piperacillin/tazobactam does not appear to enhance the prophylactic benefit of parenteral antibiotics alone.

Topical antibiotic prophylaxis for bacteremia after dental extractions.

OBJECTIVE: Current prophylaxis for endocarditis in patients undergoing dental procedures consists of oral administration of amoxicillin. There is concern that the risk of anaphylaxis from systemically administered antibiotics might approach the incidence of endocarditis. Emergence of resistance among bacteria is also favored by systemically administered antibiotics. The present study was designed to assess the efficacy of topical amoxicillin given prophylactically as a mouthwash in reducing the incidence of bacteremia after dental extraction. STUDY DESIGN: Thirty-six outpatients in a dental clinic were randomized in a 3:2:2 ratio to experimental prophylaxis of topical amoxicillin (3 g per mouthwash rinse; 15 patients), standard prophylaxis of oral amoxicillin (3 g in a single dose; 11 patients), or no prophylaxis (10 patients), respectively. Patients were stratified by severity of periodontal disease and number of teeth extracted. Data were analyzed for differences in the incidence of bacteremia by means of the 2-tailed Fisher exact test. RESULTS: Breakthrough bacteremia after dental extraction was observed in 60% (6 of 10 patients) who received topical amoxicillin and in 89% (8 of 9 patients) who received no prophylaxis (P =.30). By comparison, breakthrough bacteremia after dental extraction was observed in 10% (1 of 10 patients) who received standard prophylaxis with oral amoxicillin (60% vs 10%; P =.05). CONCLUSIONS: Topical amoxicillin decreased the incidence of bacteremia in comparison with no prophylaxis, but statistical significance was not achieved (P =.30). Topical amoxicillin was significantly less effective than standard prophylaxis with oral amoxicillin in decreasing the incidence of bacteremia after dental extractions.