Wonhee So

Pharmacodynamic Profile of GSK2140944 against Methicillin-Resistant Staphylococcus aureus in a Murine Lung Infection Model

ABSTRACT GSK2140944 is a novel bacterial type II topoisomerase inhibitor with in vitro activity against key causative respiratory pathogens, including methicillin-resistant Staphylococcus aureus (MRSA). We described the pharmacodynamics of GSK2140944 against MRSA in the neutropenic murine lung infection model. MICs of GSK2140944 were determined by broth microdilution. Plasma and epithelial lining fluid (ELF) pharmacokinetics were evaluated to allow determination of pulmonary distribution. Six MRSA isolates were tested. GSK2140944 doses of 1.56 to 400 mg/kg of body weight every 6 h (q6h) were utilized. Efficacy as the change in log10 CFU at 24 h compared with 0 h controls and the area under the concentration-time curve for the free, unbound fraction of a drug (fAUC)/MIC required for various efficacy endpoints were determined. GSK2140944 MICs were 0.125 to 0.5 mg/liter against the six MRSA isolates. ELF penetration ratios ranged from 1.1 to 1.4. Observed maximal decreases were 1.1 to 3.1 log10 CFU in neutropenic mice. The mean fAUC/MIC ratios required for stasis and 1-log-unit decreases were 59.3 ± 34.6 and 148.4 ± 83.3, respectively. GSK2140944 displayed in vitro and in vivo activity against MRSA. The pharmacodynamic profile of GSK2140944, as determined, supports its further development as a potential treatment option for pulmonary infections, including those caused by MRSA.

Effects of Urine Matrix and pH on the Potency of Delafloxacin and Ciprofloxacin against Urogenic Escherichia coli and Klebsiella pneumoniae

PURPOSE We assessed the effects of the urine matrix and its varying pH on the potency of the novel broad-spectrum fluoroquinolone delafloxacin and of ciprofloxacin against 16 urogenic Enterobacteriaceae in the urine of patients with suspected urinary tract infection. MATERIALS AND METHODS We determined minimum inhibitory concentrations in broth and urine using microdilution in 9 Escherichia coli and 7 Klebsiella pneumoniae specimens. The change in potency between broth and urine was calculated. RESULTS Against 16 highly ciprofloxacin resistant Enterobacteriaceae with a broth minimum inhibitory concentration of 32 mg/l or greater the minimum inhibitory concentration in delafloxacin in broth was 2 mg/l (1 and 0 isolates of E. coli and K. pneumoniae, respectively), 4 mg/l (3 and 0), 8 mg/l (3 and 1), 16 mg/l (2 and 4) and 32 mg/l (0 and 2). Across the 143 collected urines pH ranged from 4.7 to 9.0 with 71% at pH 6.5 or less. The delafloxacin minimum inhibitory concentration measured in 80% urine from 100 unique patient samples (pH 5.0 to 8.3) was 2 mg/l or less (18% and 0.8% for E. coli and K. pneumoniae, respectively), 4 mg/l (23% and 6%), 8 mg/l (21% and 18%), 16 mg/l (23% and 33%) and 32 mg/l or greater (15% and 42%). For E. coli and K. pneumoniae combined the median changes in the delafloxacin minimum inhibitory concentration were a 1 doubling dilution decrease at pH 6.0 or less, no change at pH 6.1 to 7.0 and a 1 doubling dilution increase at pH 7.1 or greater. Unlike delafloxacin, ciprofloxacin showed a 1 doubling dilution increase for E. coli and no change for K. pneumoniae at pH 7.0 or less with no change observed at pH 7.1 or greater. CONCLUSIONS Most urines collected from patients with urinary tract infection had a pH of 6.5 or less. Delafloxacin broth minimum inhibitory concentrations were twofold to fivefold doubling dilutions lower than those of ciprofloxacin. In contrast to ciprofloxacin, the potency of delafloxacin was further enhanced in the acidic environment commonly observed in the setting of urinary tract infection.

Antibacterial activity of achievable epithelial lining fluid exposures of Amikacin Inhale with or without meropenem

OBJECTIVES While Amikacin Inhale (BAY41-6551), an integrated drug-device combination under development, achieves an estimated amikacin epithelial lining fluid (ELF) concentration of ∼ 5000 mg/L, its target site pharmacodynamics are unknown. We evaluated the pharmacodynamics of ELF exposure of inhaled amikacin ± meropenem. METHODS ELF exposures of inhaled amikacin (400 mg every 12 h), intravenous meropenem (2 g every 8 h) and a combination of both were studied in an in vitro pharmacodynamic model. Seven Klebsiella pneumoniae and 10 Pseudomonas aeruginosa with amikacin/meropenem MICs of 1 to 32,768/≤ 0.125 to >128 mg/L were included. Efficacy was assessed over 24-72 h. RESULTS The mean ± SD 0 h bacterial density was 6.5 ± 0.1 log10 cfu/mL. Controls grew to 8.0 ± 0.5 log10 cfu/mL by the end of the experiments. Simulation of inhaled amikacin monotherapy rapidly achieved and sustained bactericidal activity near the limit of detection over 24 h for all 13 isolates with amikacin MIC ≤ 256 mg/L except only ∼ 2 log10 cfu/mL reduction was observed in K. pneumoniae 375 (amikacin/meropenem MIC 64/32 mg/L) and P. aeruginosa 1544 (amikacin/meropenem MIC 64/128 mg/L). No activity was seen against the three isolates with amikacin MIC ≥ 2048 mg/L. Among the six isolates tested with meropenem monotherapy, five (meropenem MIC ≥ 16 mg/L) grew similarly to the controls while one (meropenem MIC 2 mg/L) achieved ∼ 2.5 log10 cfu/mL decrease. Among seven isolates tested in combination, four (amikacin/meropenem MIC ≤ 64/32 mg/L), including K. pneumoniae 375, maintained limit of detection until 72 h, whereas P. aeruginosa 1544 sustained a 1 log reduction. Combination therapy had no activity against the two isolates with amikacin MIC ≥ 2048 mg/L. CONCLUSIONS Inhaled amikacin monotherapy showed bactericidal activity against most isolates tested with amikacin MICs ≤ 256 mg/L. Adjunct inhaled amikacin plus meropenem sustained this activity for 72 h for the tested isolates with amikacin/meropenem MIC ≤ 64/32 mg/L.

In Vitro Activity of Human-Simulated Epithelial Lining Fluid Exposures of Ceftaroline, Ceftriaxone, and Vancomycin against Methicillin-Susceptible and -Resistant Staphylococcus aureus

ABSTRACT Staphylococcus aureus, including methicillin-susceptible (MSSA) and -resistant (MRSA) strains, is an important pathogen of bacterial pneumonia. As antibiotic concentrations at the site of infection are responsible for killing, we investigated the activity of human-simulated epithelial lining fluid (ELF) exposures of three antibiotics (ceftaroline, ceftriaxone, and vancomycin) commonly used for treatment of S. aureus pneumonia. An in vitro pharmacodynamic model was used to simulate ELF exposures of vancomycin (1 g every 12 h [q12h]), ceftaroline (600 mg q12h and q8h), and ceftriaxone (2 g q24h and q12h). Four S. aureus isolates (2 MSSA and 2 MRSA) were evaluated over 72 h with a starting inoculum of ∼106 CFU/ml. Time-kill curves were constructed, and microbiological response (change in log10 CFU/ml from 0 h and the area under the bacterial killing and regrowth curve [AUBC]) was assessed in duplicate. The change in 72-h log10 CFU/ml was largest for ceftaroline q8h (reductions of >3 log10 CFU/ml against all strains). This regimen also achieved the lowest AUBC against all organisms (P < 0.05). Vancomycin produced reliable bacterial reductions of 0.9 to 3.3 log10 CFU/ml, while the activity of ceftaroline q12h was more variable (reductions of 0.2 to 2.3 log10 CFU/ml against 3 of 4 strains). Both regimens of ceftriaxone were poorly active against MSSA tested (0.1 reduction to a 1.8-log10 CFU/ml increase). Against these S. aureus isolates, ELF exposures of ceftaroline 600 mg q8h exhibited improved antibacterial activity compared with ceftaroline 600 mg q12h and vancomycin, and therefore, this q8h regimen deserves further evaluation for the treatment of bacterial pneumonia. These data also suggest that ceftriaxone should be avoided for S. aureus pneumonia.

Comparison of In Vivo and In Vitro Pharmacodynamics of a Humanized Regimen of 600 Milligrams of Ceftaroline Fosamil Every 12 Hours against Staphylococcus aureus at Initial Inocula of 106 and 108 CFU per Milliliter

ABSTRACT In light of the in vivo/in vitro discordance among beta-lactams against Gram-negative pathogens, we compared the in vivo pharmacodynamics of humanized ceftaroline against 9 Staphylococcus aureus strains (MICs of 0.13 to 1 mg/liter) from published in vitro studies using standard and high inocula in the murine thigh infection model. Consistent with the in vitro findings, mean reductions of ≥1 log10 CFU were observed for ceftaroline against all strains using both standard and high inocula. These results suggest in vivo/in vitro concordance with no observed inoculum effect.

Tissue penetration and exposure of cefepime in patients with diabetic foot infections

Cefepime is commonly used to treat diabetic foot infection DFIs) caused by Gram-positive and Gram-negative organisms ncluding Pseudomonas aeruginosa. Although understanding the xposure of an antibiotic at the site of infection is critical for roper dosage selection, tissue exposure of cefepime has not been escribed. In this study, the tissue exposures of cefepime were evalated by in vivo microdialysis in five hospitalised patients receiving efepime 1–2 g every 8 h (q8h) for their DFI in an open-label pharacokinetic study. Steady-state serum and microdialysis samples were collected ourly over the dosing interval as previously described [1]. Microialysis catheters were calibrated for each patient at the end f sampling using the in vivo retrodialysis technique, and perent recovery was calculated using the following equation: % ecovery in vivo = 100 − (100 × Cdialysate/Cperfusate), where Cdialysate nd Cperfusate are the concentrations of cefepime in the dialysate nd perfusate, respectively. Protein binding was determined in riplicate by ultrafiltration for each patient at the beginning, midoint and end of the dosing interval as previously described 1]. Cefepime concentrations in serum and dialysate were deterined using a validated high-performance liquid chromatography HPLC) assay that was developed using a previously published ssay at the Center for Anti-Infective Research and Development Hartford, CT) [2]. The cefepime concentration in interstitial tissue fluid (Ctissue) as calculated by the equation: Ctissue = 100 × (Cdialysate/% recovry in vivo) [1]. The half-life (t1/2) was calculated from both otal drug concentration in serum (Cserum) and Ctissue as ln(2)/ z, here z is the terminal elimination rate constant that was estiated by linear regression analysis of the terminal portion of the

Physical compatibility of isavuconazonium sulfate with select i.v. drugs during simulated Y-site administration

PURPOSE The physical compatibility of isavuconazonium sulfate with 95 i.v. drugs during simulated Y-site administration was studied. METHODS Isavuconazonium sulfate for injection and all other drugs were reconstituted according to the manufacturers recommendation and further diluted with 0.9% sodium chloride injection or 5% dextrose injection to a final concentration (1.5 mg/mL for isavuconazonium sulfate and standard concentrations used clinically for other drugs). A Y site was simulated in glass culture tubes by mixing 5 mL of the tested drug and isavuconazonium sulfate solutions in each diluent. Incompatibility was defined as changes in visual characteristics or increases in turbidity by greater than 0.5 nephelometric turbidity units over the 120-minute experiment. RESULTS Of the 95 drugs tested, isavuconazonium sulfate was physically compatible with 66 drugs in 0.9% sodium chloride injection and 60 drugs in 5% dextrose injection. Incompatibility was observed with albumin, amphotericin B deoxycholate, amphotericin B lipid complex, amphotericin B liposome, ampicillin-sulbactam, cefazolin, cefepime, ceftaroline fosamil, ceftazidime, ceftriaxone, cefuroxime, colistimethate sodium, cyclosporine, ertapenem, esomeprazole, filgrastim, fosphenytoin, furosemide, heparin, meropenem, methylprednisolone, micafungin, phenytoin, potassium phosphate, propofol, sodium bicarbonate, sodium phosphate, and tedizolid. Azithromycin, bumetanide, penicillin G potassium, and piperacillin-tazobactam were incompatible with isavuconazonium sulfate in 5% dextrose injection only. CONCLUSION Of the 95 drugs tested, isavuconazonium sulfate 1.5 mg/mL was physically compatible with 66 drugs in 0.9% sodium chloride injection and 60 drugs in 5% dextrose injection. Incompatibility was observed with 18 antimicrobials, including most cephalosporins tested, and 14 other i.v. drugs in at least 1 of the 2 tested diluents.