Safety, tolerability, pharmacokinetics, and pharmacodynamics of oral JNJ-64794964, a TLR-7 agonist, in healthy adults.

BACKGROUND: This Phase I, two-part, first-in-human study assessed safety/tolerability and pharmacokinetics/pharmacodynamics of single-ascending doses (SAD) and multiple doses (MD) of the oral toll-like receptor-7 agonist, JNJ-64794964 (JNJ-4964) in healthy adults. METHODS: In the SAD phase, participants received JNJ-4964 0.2 (N = 6), 0.6 (N = 6), 1.25 (N = 8) or 1.8 mg (N = 6) or placebo (N = 2/dose cohort) in a fasted state. Food effect was evaluated for the 1.25 mg cohort following ≥6 weeks washout. In the MD phase, participants received JNJ-4964 1.25 mg (N = 6) or placebo (N = 2) weekly (fasted) for 4 weeks. Participants were followed-up for 4 weeks. RESULTS: No serious adverse events (AEs) occurred. 10/34 (SAD) and 5/8 (MD) participants reported mild-to-moderate (≤Grade 2), transient, reversible AEs possibly related to JNJ-4964. Five (SAD) participants had fever/flu-like AEs, coinciding with interferon-α serum levels ≥100 pg/mL and lymphopenia (<1 × 109/L), between 24-48 h after dosing and resolving approximately 96 h after dosing. One participant (MD) had an asymptomatic Grade 1 AE of retinal exudates (cotton wool spots) during follow-up, resolving 6 weeks after observation. JNJ-4964 exhibited dose-proportional pharmacokinetics, with rapid absorption (tmax 0.5-0.75 h) and distribution, and a long terminal half-life (150-591 h). Overall, no significant differences in JNJ-4964 pharmacokinetic parameters were observed in the fed versus fasted state. JNJ-4964 dose-dependently and transiently induced cytokines with potential anti-HBV activity, including interferon-α, IP-10, IL-1 RA, and/or MCP-1, and interferon-stimulated genes (ISG15, MX1, and OAS1) in serum. CONCLUSIONS: In healthy adults, JNJ-4964 was generally well-tolerated, exhibited dose-proportional pharmacokinetics and induced cytokines/ISGs, with possible anti-HBV activity.

Recurrent furunculosis caused by a community-acquired Staphylococcus aureus strain belonging to the USA300 clone.

BACKGROUND: A 24-year-old female with recurrent skin and soft tissue infections (SSTI) was enrolled as part of a multicenter observational cohort study conducted by a practice-based research network (PBRN) on community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA). METHODS: Strains were characterized by pulsed-field gel electrophoresis (PFGE), spa typing, and multilocus sequence typing. MRSA strains were analyzed for SCCmec type and the presence of the Panton-Valentine leukocidin (PVL) and arginine catabolic mobile element (ACME) using PCR. RESULTS: In the first episode, S. aureus was recovered from the wound and inguinal folds; in the second, S. aureus was recovered from a lower abdomen furuncle, inguinal folds, and patellar fold. Molecular typing identified CA-MRSA clone USA300 in all samples as spa-type t008, ST8, SCCmecIVa, and a typical PFGE pattern. The strain carried virulence genes pvl and ACME type I. Five SSTI episodes were documented despite successful resolution by antibiotic treatment, with and without incision and drainage. CONCLUSIONS: The source of the USA300 strain remains unknown. The isolate may represent a persistent strain capable of surviving extensive antibiotic pressure or a persistent environmental reservoir may be the source, possibly in the patient's household, from which bacteria were repeatedly introduced into the skin flora with subsequent infections.

Salmonella neck abscess as an opportunistic infection in diabetes mellitus.

Salmonella neck infections represent an uncommon cause of focal salmonellosis. While the incidence of nontyphoid salmonellosis is estimated at over 2 million cases annually, extraintestinal manifestations account for less than 1% of cases. This paper describes two patients with Salmonella neck abscesses as the initial presentation of diabetes mellitus. The first patient was diagnosed as having Salmonella enterica serotype Enteritidis sternocleidomastoid pyomyositis and the second patient Salmonella enterica serotype Typhimurium parapharyngeal abscess. Both patients had elevated hemoglobin A1c levels and had not been previously diagnosed with diabetes mellitus. Salmonella spp. should be on the differential as a causative pathogen in patients presenting with neck abscesses and poorly controlled glucose levels. Diabetes may be a risk factor for salmonellosis due to decreased gastric acidity and prolonged gastric transit time. Prompt incision and drainage accompanied by antibiotics remains the treatment of choice for infected neck abscesses.

Lysins: the arrival of pathogen-directed anti-infectives.

Lysins represent a novel class of anti-infectives derived from bacteriophage. Lysins are bacterial cell-wall hydrolytic enzymes that selectively and rapidly kill (≥3 log c.f.u. in 30 min) specific Gram-positive bacteria providing a targeted therapeutic approach with minimal impact on unrelated commensal flora. The potential for bacterial resistance to lysins is considered low due to targeting of highly conserved peptidoglycan components. Through cutting-edge genetic engineering, lysins can be assembled into large libraries of anti-infective agents tailored to any bacterium of interest including drug-resistant Gram-positive pathogens such as meticillin- and vancomycin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus faecalis and Enterococcus faecium, and penicillin-resistant Streptococcus pneumoniae. Lysins can eliminate bacteria systemically and topically from mucosal surfaces and biofilms, as evidenced by experimental models of sepsis, endocarditis, pneumonia, meningitis, and nasopharyngeal, skin and vaginal decolonization. Furthermore, lysins can act synergistically with antibiotics and, in the process, resensitize bacteria to non-susceptible antibiotics. Clinical trials are being prepared to assess the safety and pharmacokinetic properties of lysins in humans.

Predicting risk for death from MRSA bacteremia.

Methicillin-resistant Staphylococcus aureus (MRSA) bacteremia is often fatal. To determine predictors of risk for death, we conducted a retrospective cohort study. We examined 699 episodes of MRSA bacteremia involving 603 patients admitted to an academic medical center in New York City during 2002-2007. Data came from chart reviews, hospital databases, and recultured frozen MRSA specimens. Among the 699 episodes, 55 were caused by vancomycin-intermediate resistant S. aureus strains, 55 by heteroresistant vancomycin-intermediate S. aureus strains, and 589 by non-vancomycin-resistant strains; 190 (31.5%) patients died. We used regression risk analysis to quantify the association between clinical correlates and death. We found that older age, residence in a nursing home, severe bacteremia, and organ impairment were independently associated with increased risk for death; consultation with an infectious disease specialist was associated with lower risk for death; and MRSA strain types were not associated with risk for death.

A novel chimeric lysin shows superiority to mupirocin for skin decolonization of methicillin-resistant and -sensitive Staphylococcus aureus strains.

Staphylococcus aureus is a major human pathogen responsible for a number of serious and sometimes fatal infections. One of its reservoirs on the human body is the skin, which is known to be a source of invasive infection. The potential for an engineered staphylococcus-specific phage lysin (ClyS) to be used for topical decolonization is presented. We formulated ClyS into an ointment and applied it to a mouse model of skin colonization/infection with S. aureus. Unlike the standard topical antibacterial agent mupirocin, ClyS eradicated a significantly greater number of methicillin-susceptible S. aureus (MSSA) and -resistant S. aureus (MRSA) bacteria: a 3-log reduction with ClyS as opposed to a 2-log reduction with mupirocin in our model. The use of ClyS also demonstrated a decreased potential for the development of resistance by MRSA and MSSA organisms compared to that from the use of mupirocin in vitro. Because antibodies may affect enzyme function, we tested antibodies developed after repeated ClyS exposure for their effect on ClyS killing ability. Our results showed no inhibition of ClyS activity at various antibody titers. These data demonstrate the potential of developing ClyS as a novel class of topical antimicrobial agents specific to staphylococcus.

Disseminated cryptococcosis resulting in miscarriage in a woman without other immunocompromise: a case report.

We present an unusual case of disseminated cryptococcosis involving the lungs, placenta, and gall bladder in an apparently immunocompetent pregnant woman. The infection resulted in spontaneous abortion. The patient's condition only improved after cholecystectomy and several weeks of antifungal therapy. An in-depth evaluation revealed no central nervous system involvement or immunocompromising condition other than pregnancy.

Klebsiella pneumoniae liver abscesses in a public hospital in Queens, New York.

BACKGROUND: Klebsiella pneumoniae liver abscess has been described frequently in patients residing in Asian countries. With the advent of immigration, this disease has become more common in certain hospitals in the United States, based upon the demographics of their patient populations. METHODS: We reviewed laboratory and clinical data for patients admitted to a municipal hospital in Queens, New York from 2000 to 2007 via a retrospective chart review. RESULTS: Of the 56 cases of pyogenic liver abscess reviewed, 20 cases were secondary to Klebsiella pneumoniae, verified via radiographic imaging plus positive blood culture or liver aspiration culture. Of these cases, 60% of patients were of Asian descent. Liver drainage appeared to be the most important modality of treatment. Choice of antibiotics and duration of treatment varied greatly depending upon whether an infectious disease consultant was called or not. CONCLUSIONS: The majority of community-acquired Klebsiella pneumoniae liver abscess occurred in patients of Asian descent. Many of these patients have not resided in their country of origin for quite some time. In hospitals serving large Asian populations, this diagnosis must be considered and appropriate work-up for metastatic complications should be provided promptly.