Safety and pharmacokinetics of XOMA 3AB, a novel mixture of three monoclonal antibodies against botulinum toxin A.

Botulinum neurotoxin A is a category A bioterrorism agent. Current antitoxin therapies are scarce and produce adverse reactions. XOMA 3AB consists of 3 IgG1 monoclonal antibodies (MAbs), each with a distinct human or humanized variable region, which bind to distinct epitopes on botulinum neurotoxin serotype A. This first-in-human study evaluated the safety and pharmacokinetics (PK) of escalating doses of XOMA 3AB administered intravenously (i.v.) to healthy adults. In this double-blind placebo-controlled dose escalation study, 3 cohorts of 8 healthy subjects received a single intravenous dose of XOMA 3AB or placebo at a 3:1 ratio. Follow-up examinations included physical examinations, hematology and chemistry blood tests, electrocardiograms, and pharmacokinetics. Pharmacokinetic parameters were estimated using noncompartmental methods. There were no infusion discontinuations or hypersensitivity reactions. Two or more subjects experienced headache, hyperglycemia, or anemia; none was dose related. All adverse events (AEs) were mild to moderate except for an episode of exercise-induced elevation of a subject's creatine phosphokinase (CPK) level, unrelated to XOMA 3AB. Concentration-time plots demonstrated a peak in MAb concentrations 1 to 2 h after completion of the infusion, after which the levels declined in a biexponential decay pattern for all analytes. For each MAb, the maximum concentration of drug in serum (Cmax) and the area under the concentration-time curve from 0 to infinity (AUCinf) increased as the dose increased. Clearance of the humanized mouse MAb was more rapid than that of the two fully human MAbs, particularly at the lowest dose. None of the MAbs was immunogenic. At the doses administered, XOMA 3AB was well tolerated. These safety findings support further investigation of XOMA 3AB as a potential agent for botulism treatment and postexposure prophylaxis. (This study has been registered at ClinicalTrials.gov under registration no. NCT01357213.).

PCR offers no advantage over culture for microbiologic diagnosis in cellulitis.

PURPOSE: Most cases of cellulitis are traditionally attributed to ß-hemolytic Streptococcus and Staphylococcus species, although in most cases, no organism is identified. Development of PCR using the conserved bacterial 16 S rRNA DNA permits identification of bacteria independent of conventional culture approaches and prior use of antibiotics. METHODS: We used PCR-based techniques to identify cellulitis etiology using aspirate samples from affected skin. Saline was infiltrated and aspirated at the site of greatest erythema or at the cellulitic border. Samples were tested for 16 S rRNA DNA, and organism-specific probes used to identify bacteria commonly seen in skin infections. RESULTS: Aspirates from 32 patients were studied, and 16 S rRNA DNA was detected in nine of these patient samples (28.1%). Bacterial species were identified by PCR methods in six of these nine samples (66.6%), with S. aureus and methicillin-resistant S. aureus (MRSA) identified in four and two, respectively, of these samples. Of the patients with positive aspirate bacterial cultures (3/9, 33.3%), S. aureus and coagulase-negative Staphylococcus (CoNS) were present on cultures of two of the three (both 66.6%) positive samples. Only in one of the three positive bacterial cultures did the PCR method detect the same organism as was detected by culture. Among patients with positive provider-collected clinical cultures, MRSA was the predominant organism (11/18, 61.1%) and when present, it was found as the sole organism. Where S. aureus or Streptococcus species were detected by molecular methods, clinical cultures yielded a positive result as well. CONCLUSIONS: PCR-based techniques do not appear to be more sensitive than aspirate cultures for the detection of pathogens in cellulitis.

Real-time PCR assays compared to culture-based approaches for identification of aerobic bacteria in chronic wounds.

Chronic wounds cause substantial morbidity and disability. Infection in chronic wounds is clinically defined by routine culture methods that can take several days to obtain a final result, and may not fully describe the community of organisms or biome within these wounds. Molecular diagnostic approaches offer promise for a more rapid and complete assessment. We report the development of a suite of real-time PCR assays for rapid identification of bacteria directly from tissue samples. The panel of assays targets 14 common, clinically relevant, aerobic pathogens and demonstrates a high degree of sensitivity and specificity using a panel of organisms commonly associated with chronic wound infection. Thirty-nine tissue samples from 29 chronic wounds were evaluated and the results compared with those obtained by culture. As revealed by culture and PCR, the most common organisms were methicillin-resistant Staphylococcus aureus (MRSA) followed by Streptococcus agalactiae (Group B streptococcus) and Pseudomonas aeruginosa. The sensitivities of the PCR assays were 100% and 90% when quantitative and qualitative culture results were used as the reference standard, respectively. The assays allowed the identification of bacterial DNA from ten additional organisms that were not revealed by quantitative or qualitative cultures. Under optimal conditions, the turnaround time for PCR results is as short as 4-6 h. Real-time PCR is a rapid and inexpensive approach that can be easily introduced into clinical practice for detection of organisms directly from tissue samples. Characterization of the anaerobic microflora by real-time PCR of chronic wounds is warranted.