Dolutegravir (DTG) is a once-daily, unboosted integrase inhibitor that has been shown to be effective by once daily dosing. The impact of race on dolutegravir pharmacokinetics has not yet been fully characterized. This study was a Phase 1, open label, single dose study to determine pharmacokinetics (PK), safety and tolerability of DTG following 50mg single oral administration in the fasted state in healthy adult Japanese subjects. Subjects had a screening visit within 30 days prior to the administration of study drug, and a follow-up visit within 7 to 14 days after the administration of study drug. Safety evaluation and serial PK samplings were performed pre-dose and for 72 hours after dosing. Non-compartmental analysis was performed for PK parameter calculation. Data were compared to historical values from a similar Phase 1 study conducted in non-Asian, healthy adult subjects (n=18, 17 Caucasian and 1 Arabic/North African). Ten subjects were enrolled and completed the study. DTG was well tolerated with no adverse events reported throughout the study period. Geometric means (CV%) of single dose DTG PK parameters in Japanese subjects for C_max, AUC_inf, t_1/2 and C₂₄ were 2.14𝜇g/mL (47%, 43.4𝜇g·hr/mL (46%), 14.6 hours (10%) and 0.67𝜇g/mL (45%). The pharmacokinetics and safety profiles of DTG following single dose oral administration to Japanese healthy adult subjects were consistent with findings previously observed in non-Japanese healthy adult subjects. DTG may be given to Japanese subjects without dose-adjustment.

The initial bactericidal activity of quinolones against Streptococcus pneumoniae at the concentration equivalent to their respective peak serum concentration (C_max) and free drug fraction of C_max (fC_max) were investigated. The bactericidal activity of sitafloxacin (STFX), levofloxacin (LVFX), moxifloxacin (MFLX), and garenoxacin (GRNX) were compared by determining the actual killing of bacteria at C_max and fC_max for 1 and 2 hours based on the Japanese maximum dose per administration (100, 500, 400, and 400mg, respectively). Against 4 quinolone-susceptible clinical isolates (wild-type), STFX with C_max and fC_max exhibited the most rapid bactericidal activity resulting in an average reduction of ≥3.0log₁₀ colony forming units (CFU)/ mL in 1 hour. STFX with C_max and fC_max also showed the most rapid and potent bactericidal activity against 9 clinical isolates with single par (C/E) mutation, resulting in ≥3.0log₁₀ CFU/mL average reduction in viable cells in 1 hour. STFX showed a statistically significant advantage in initial bactericidal activity over other quinolones for single mutants (P<0.001). The propensity that the difference in the initial bactericidal activity between STFX and other quinolones was higher in single mutants than wild-type strains, was confirmed using S. pneumoniae ATCC49619 (wild-type) and its laboratory single parC mutant. As a result, STFX showed a similar rapid and potent initial bactericidal activity against both strains, while initial bactericidal activity for other quinolones was significantly reduced in the single mutant (P<0.05). In conclusion, STFX has the most rapid and potent initial bactericidal activity against wild-type and single mutants of S. pneumoniae and its bactericidal activity is not affected by the presence of a single par mutation compared to LVFX, MFLX, and GRNX.

We conducted a study assess the bactericidal activity of sitafloxacin (STFX) against Streptococcus pneumoniae isolates recovered from respiratory infections including penicillinresistant(PRSP) isolates, macrolide resistant isolates possessing mefA and ermB resistance genes and quinolone resistance isolates with mutations in gyrA or gyrA and parC. Each isolate tested was grown in hemosupplemented Mueller-Hinton broth and adjusted to approximately 105 CFU/mL. Isolates were than exposed to a Cmax antimicrobial blood level that would be attained with routine antimicrobial administration and an antimicrobial level that would be expected 4 hours post-Cmax (Cmax 4 hr). Bactericidal activity was measured for up to 8 hours. Excluding a subset of S. pneumoniae isolates with mutations in the quinolone resistance determining region (QRDR), all quinolones showed bactericidal activity at Cmax and Cmax 4 hr antimicrobial concentrations for up to 8 hours. Against S. pneumoniae isolates with either gyrA or gyrA and parC mutations, bactericidal activity of STFX was shown for up to 4 to 8 hours following Cmax based on a limit of detection of <1.3 log CFU/mL. Garenoxacin (GRNX) did not showed bactericidal activity below the limit of detection for up to 8 hours with exposure to Cmax and no bactericidal activity was seen with levofloxacin.

When all quinolones tested where adjusted to concentrations corresponding to their MICs, STFX showed the most rapid bactericidal activity against PRSP. This rapid bactericidal activity in PRSP is a key to the effectiveness of STFX. Our findings show that beyond inhibition of bacterial replication by blocking their DNA replication pathway and synthesis of proteins, STFX demonstrated characteristics contributing to greater bactericidal activity compared to GRNX.

In conclusion, of the newer quinolones, STFX showed the strongest bactericidal activity against S. pneumoniae isolates with mutations in the QRDR which indicates that it may show the most effective clinical utility among the quinolones in respiratory infections.

We report a case of pulmonary aspergillosis in lung transplant recipient who was successfully treated with inhalation administration of anti-fungal agent. The case was 33-year-old female. Two years ago, she had received lung transplant because of lymphangioleiomyomatosis. One year ago, she had diagnosed of pulmonary aspergillosis and successfully treated with micafungin and itraconazole. Then she had been continuous administered with itraconazole. In June 20xx, she had nausea and vomiting and was diagnosed of viral enteritis. Although abdominal symptoms were relieved, ground glass opacity was discovered in her right lung. Bronchoscopic examination revealed ulceration of bronchus with white necrotic substance. Laboratory culture test demonstrated Aspergillus spp. Finally she was diagnosed of recurrent pulmonary aspergillosis. First, she was treated with intravascular administration of micafungin. Then, inhalation administration of liposomal amphotericin B was changed. Ground glass opacity and bronchial region of pulmonary aspergillosis was improved. Thereafter, inhalation of amphotericin B was continued and no recurrence of pulmonary aspergillosis has been found. Inhalation of anti-fungal agent could be an option for pulmonary aspergillosis.