The Fluorocycline TP-271 Is Efficacious in Models of Aerosolized Bacillus anthracis Infection in BALB/c Mice and Cynomolgus Macaques.

The fluorocycline TP-271 was evaluated in mouse and nonhuman primate (NHP) models of inhalational anthrax. BALB/c mice were exposed by nose-only aerosol to Bacillus anthracis Ames spores at a level of 18 to 88 lethal doses sufficient to kill 50% of exposed individuals (LD50). When 21 days of once-daily dosing was initiated at 24 h postchallenge (the postexposure prophylaxis [PEP] study), the rates of survival for the groups treated with TP-271 at 3, 6, 12, and 18 mg/kg of body weight were 90%, 95%, 95%, and 84%, respectively. When 21 days of dosing was initiated at 48 h postchallenge (the treatment [Tx] study), the rates of survival for the groups treated with TP-271 at 6, 12, and 18 mg/kg TP-271 were 100%, 91%, and 81%, respectively. No deaths of TP-271-treated mice occurred during the 39-day posttreatment observation period. In the NHP model, cynomolgus macaques received an average dose of 197 LD50 of B. anthracis Ames spore equivalents using a head-only inhalation exposure chamber, and once-daily treatment of 1 mg/kg TP-271 lasting for 14 or 21 days was initiated within 3 h of detection of protective antigen (PA) in the blood. No (0/8) animals in the vehicle control-treated group survived, whereas all 8 infected macaques treated for 21 days and 4 of 6 macaques in the 14-day treatment group survived to the end of the study (56 days postchallenge). All survivors developed toxin-neutralizing and anti-PA IgG antibodies, indicating an immunologic response. On the basis of the results obtained with the mouse and NHP models, TP-271 shows promise as a countermeasure for the treatment of inhalational anthrax.

The Fluorocycline TP-271 Is Efficacious in Models of Aerosolized Francisella tularensis SCHU S4 Infection in BALB/c Mice and Cynomolgus Macaques.

TP-271 is a novel, fully synthetic fluorocycline in development for complicated bacterial respiratory infections. TP-271 was active in vitro against a panel of 29 Francisella tularensis isolates, showing MICs against 50% and 90% of isolates of 0.25 and 0.5 µg/ml, respectively. In a mouse model of inhalational tularemia, animals were exposed by aerosol to 91 to 283 50% lethal doses (LD50)/mouse of F. tularensis SCHU S4. Following 21 days of once-daily intraperitoneal dosing with TP-271 at 3, 6, 12, and 18 mg/kg of body weight/day, initiating at 24 h postchallenge, survival was 80%, 100%, 100%, and 100%, respectively. When treatment was initiated at 72 h postchallenge, survival was 89%, 100%, 100%, and 100% in the 3-, 6-, 12-, and 18-mg/kg/day TP-271 groups, respectively. No mice treated with the vehicle control survived. Surviving mice treated with TP-271 showed little to no relapse during 14 days posttreatment. In a nonhuman primate model of inhalational tularemia, cynomolgus macaques received an average aerosol exposure of 1,144 CFU of F. tularensis SCHU S4. Once-daily intravenous infusion with 1 or 3 mg/kg TP-271, or vehicle control, for 21 days was initiated within 6 h of confirmed fever. All animals treated with TP-271 survived to the end of the study, with no relapse during 14 days after the last treatment, whereas no vehicle control-treated animals survived. The protection and low relapse afforded by TP-271 treatment in these studies support continued investigation of TP-271 for use in the event of aerosolized exposure to F. tularensis.

Eravacycline (TP-434) is efficacious in animal models of infection.

Eravacycline is a novel broad-spectrum fluorocycline antibiotic being developed for a wide range of serious infections. Eravacycline was efficacious in mouse septicemia models, demonstrating 50% protective dose (PD50) values of ≤ 1 mg/kg of body weight once a day (q.d.) against Staphylococcus aureus, including tetracycline-resistant isolates of methicillin-resistant S. aureus (MRSA), and Streptococcus pyogenes. The PD50 values against Escherichia coli isolates were 1.2 to 4.4 mg/kg q.d. In neutropenic mouse thigh infection models with methicillin-sensitive S. aureus (MSSA) and S. pyogenes, eravacycline produced 2 log10 reductions in CFU at single intravenous (i.v.) doses ranging from 0.2 to 9.5 mg/kg. In a neutropenic mouse lung infection model, eravacycline administered i.v. at 10 mg/kg twice a day (b.i.d.) reduced the level of tetracycline-resistant MRSA in the lung equivalent to that of linezolid given orally (p.o.) at 30 mg/kg b.i.d. At i.v. doses of 3 to 12 mg/kg b.i.d., eravacycline was more efficacious against tetracycline-resistant Streptococcus pneumoniae in a neutropenic lung infection model than linezolid p.o. at 30 mg/kg b.i.d. Eravacycline showed good efficacy at 2 to 10 mg/kg i.v. b.i.d., producing up to a 4.6 log10 CFU reduction in kidney bacterial burden in a model challenged with a uropathogenic E. coli isolate. Eravacycline was active in multiple murine models of infection against clinically important Gram-positive and Gram-negative pathogens.

Treatment with a novel topical nanoemulsion (NB-001) speeds time to healing of recurrent cold sores.

BACKGROUND: Current topical therapies for cold sores are only marginally beneficial due to poor skin penetration. We assessed the safety and efficacy of a novel topical antiviral nanoemulsion (NB-001) with high tissue bioavailability. OBJECTIVES: The primary endpoint was the time to lesion healing. METHODS: 482 subjects with recurrent cold sores were randomized to self-initiate treatment with either vehicle or NB-001 (0.1%, 0.3% or 0.5%) at the first signs or symptoms of a cold sore episode. Lotion was applied 5 times per day, approximately 3 to 4 hours apart, for 4 days. Time to lesion healing was correlated with NB-001 bioavailability determined in human cadaver skin. RESULTS: Subjects treated with 0.3% NB-001 showed a 1.3-day improvement in the mean time to healing compared to vehicle (P=0.006). This was consistent with human cadaver skin data indicating that the 0.3% nanoemulsion had the highest bioavailability, compared to 0.1% and 0.5% emulsions. No significant safety or dermal irritation concerns or systemic absorption were noted with any of the doses. CONCLUSIONS: Topical NB-001 (0.3%) was well tolerated and highly efficacious in shortening the time to healing of cold sores. The improvement in time to healing was similar to that reported for oral nucleoside analogues, but without systemic exposure. Topical agents for recurrent herpes labialis (cold sores) reduce healing time by one half day, compared to oral therapies that speed healing by a day or more. A topical antiviral nanoemulsion was well tolerated and improved cold sore healing time by over a day compared to vehicle control. Nanoemulsion (NB-001) could represent a more efficacious topical treatment for recurrent cold sores.

Improving on nature: antibiotics that target the ribosome.

Antibiotic resistance, along with the resolution of antibiotic-ribosomal subunit complexes at the atomic level, has provided new insights into modifications of clinically relevant antimicrobials that target the ribosome. Modifications to the aminoglycoside or negamycin scaffolds have been reported in the past, but few derivatives appear to be greatly improved compared to their parent compound. Computational and/or traditional screening efforts have yielded novel compounds that bind to the decoding site of the small (30S) ribosomal subunit; naphthyridones appear to bind only in the presence of poly(U) and tRNA(Phe), whereas quinolines bind in a similar manner to aminoglycosides. Streptogramin B analogs were designed that have an amide replacement of the labile ester bond. The resultant molecules were not substrates for the inactivating lyase, but were no longer inhibitors of translation. The synthesis of 16-membered macrolides that are modified at the C6 position with peptidyl moieties as well as conjugates of chloramphenicol to either nucleotide groups or pyrene have been described, but no antibacterial activity has been reported. X-ray crystal structures are now available that can be used to improve on natural or synthetic antibiotics that bind to either the 30S or the 50S ribosomal subunit.

Macrolide-resistant pneumococcal endocarditis and epidural abscess that develop during erythromycin therapy.

Suppurative complications of Streptococcus pneumoniae infections have become uncommon in the antibiotic era. We report a case of pneumococcal bacteremia and pneumonia complicated with epidural abscess and endocarditis in which macrolide resistance (the MLS(B) phenotype) emerged during erythromycin therapy. Genetic determinants known to mediate the most common mechanisms of macrolide resistance (methylation of the 23S rRNA and antibiotic efflux) were not detected by polymerase chain reaction or DNA hybridization. Sequence analysis of the DNA encoding the 23S rRNA of the macrolide-resistant isolate from the patient demonstrated the replacement of adenine by thymine at position 2058 (A2058T) in 2 of 4 alleles. Clinicians should be alert to the possibility of the emergence of resistance during macrolide therapy for community-acquired pneumonia, particularly if suppurative complications of pneumococcal infection are suspected.