Combination of Sequential Organ Failure Assessment (SOFA) score and Charlson Comorbidity Index (CCI) could predict the severity and prognosis of candidemia more accurately than the Acute Physiology, Age, Chronic Health Evaluation II (APACHE II) score.

BACKGROUND: Candidemia has emerged as an important nosocomial infection, with a mortality rate of 30-50%. It is the fourth most common nosocomial bloodstream infection (BSI) in the United States and the seventh most common nosocomial BSI in Europe and Japan. The aim of this study was to assess the performance of the Sequential Organ Failure Assessment (SOFA) score for determining the severity and prognosis of candidemia. METHODS: We performed a retrospective study of patients admitted to hospital with candidemia between September 2014 and May 2018. The severity of candidemia was evaluated using the SOFA score and the Acute Physiology, Age, Chronic Health Evaluation II (APACHE II) score. Patients' underlying diseases were assessed by the Charlson Comorbidity Index (CCI). RESULTS: Of 70 patients enrolled, 41 (59%) were males, and 29 (41%) were females. Their median age was 73 years (range: 36-93 years). The most common infection site was catheter-related bloodstream infection (n=36, 51%).The 30-day, and in-hospital mortality rates were 36 and 43%, respectively. Univariate analysis showed that SOFA score ≥5, APACHE II score ≥13, initial antifungal treatment with echinocandin, albumin < 2.3, C-reactive protein > 6, disturbance of consciousness, and CCI ≥3 were related with 30-day mortality. Of these 7, multivariate analysis showed that the combination of SOFA score ≥5 and CCI ≥3 was the best independent prognostic indicator for 30-day and in-hospital mortality. CONCLUSIONS: The combined SOFA score and CCI was a better predictor of the 30-day mortality and in-hospital mortality than the APACHE II score alone.

In vitro and in vivo antibacterial activity of nitrofurantoin against clinical isolates of E. coli in Japan and evaluation of biological cost of nitrofurantoin resistant strains using a mouse urinary tract infection model.

INTRODUCTION: Nitrofurantoin is a well-established antibiotic, and is an important first-line oral treatment for uncomplicated urinary tract infections. However, little information is available with respect to its antibacterial activity in Japan, in vivo efficacy, or the in vivo biological cost of resistant strains. METHODS: We compared the susceptibility of six representative antibacterial agents-nitrofurantoin, sulfamethoxazole/trimethoprim, fosfomycin, mecillinam, ciprofloxacin, and cefdinir-against E. coli clinically isolated in Japan during 2017. We evaluated the in vivo efficacy of nitrofurantoin using a model of mouse urinary tract infection caused by ciprofloxacin resistant E. coli. We obtained nitrofurantoin resistant isolates through tests generating spontaneous mutations, and assessed the in vivo fitness of nitrofurantoin resistant isolates. RESULTS: The MIC90 of nitrofurantoin was 16 µg/mL, and was the lowest among the drugs tested. It was found that, in the mouse urinary tract infection model, 30 mg/kg and 100 mg/kg of nitrofurantoin reduced the count of viable bacterial cells in the kidney, while 100 mg/kg of ciprofloxacin did not. All spontaneous bacterial mutants resistant to nitrofurantoin had deletions in the nfsA gene, and we found that the resistant strain had lower growth in the mouse urinary tract infection model than in the parent strain. CONCLUSIONS: We demonstrated promising in vitro and in vivo activity of nitrofurantoin against E. coli clinical isolates in Japan, and lower in vivo fitness of the resistant strain of nitrofurantoin.

A novel disk-based detection method with superior sensitivity for ß-lactamase production in third-generation cephalosporin-resistant Enterobacteriaceae.

OBJECTIVE: Current phenotypic methods for extended-spectrum ß-lactamase (ESBL), AmpC ß-lactamase (AmpC), and carbapenemases fail to detect isolates that co-produce other classes of ß-lactamases. In this study, we have developed a novel assay (Applied Multiplex Disk Method: AMU-DM) for the phenotypic detection and identification of ß-lactamases produced by Enterobacteriaceae. METHODS: We evaluated the performance of the method by comparison with PCR results for 78 Enterobacteriaceae clinical isolates that were positive by the ESBL screening test and negative by the ESBL confirmation test. Additionally, one NCTC strain and four ATCC strains were also included in the test population for the study as reference. RESULTS: For 79/83 (95%) isolates tested, the AMU-DM results matched those obtained by PCR. The concordance rates were 31/31 (100%), 11/11 (100%), 3/3 (100%), 0/1 (0%), 15/15 (100%), 16/19 (84%), and 3/3 (100%) for AmpC, ESBL and AmpC co-production, Klebsiella pneumoniae carbapenemase (KPC), KPC and ESBL co-production, metallo ß-lactamase (MBL), MBL and ESBL co-production, and MBL and AmpC co-production, respectively. CONCLUSION: The AMU-DM is convenient to perform, economical, and highly sensitive in identifying ESBLs, AmpCs, and carbapenemases. Our method may be useful in clinical settings for the implementation of relevant infection control measures and for surveillance purposes.

Proposed Pharmacokinetic-Pharmacodynamic Breakpoint of Garenoxacin and Other Quinolones.

The pharmacokinetic-pharmacodynamic (PK-PD) breakpoints (BPs) of garenoxacin (GRNX) and other oral quinolones were calculated using Monte Carlo simulation (MCS) based on the distribution of changes in their plasma concentrations. PK-PD BPs of 400 mg once a day (QD) of GRNX for the free area under the curve/minimum inhibitory concentration (fAUC/MIC) for 30 strains of Streptococcus pneumoniae and 100 strains of gram-negative bacteria (G [－]) were 0.5 and 0.125 µg/mL, respectively. PK-PD BPs of other quinolones for S. pneumoniae/G (－) were 1/0.25 µg/mL for levofloxacin (LVFX) 500 mg QD, 0.5/0.125 µg/mL for moxifloxacin (MFLX) 400 mg QD, 0.0625/0.0156 µg/mL for sitafloxacin (STFX) 50 mg twice a day (BID) (100 mg QD), and 0.125/0.0313 µg/mL for STFX 100 mg BID. We also investigated the hypothetical probability of target attainments (PTAs) of fAUC/MIC for community-acquired pneumonia (CAP) using MCS, in consideration of the isolation frequencies of the three main causative pathogens of CAP: S. pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis. For hypothetical CAP in adults, PTA of fAUC/MIC was 100% with GRNX and MFLX, 96%-97% with STFX at 100 mg BID, 45%-46% with LVFX, and 53%-58% with STFX at 100 mg QD and 50 mg BID. Based on the PK-PD BP, GRNX showed higher fAUC/MIC than the other quinolones tested against the three main pathogens of respiratory infections.

Evaluation of Amikacin Pharmacokinetics and Pharmacodynamics for Optimal Initial Dosing Regimen.

Amikacin has been one of the important antimicrobial agents against Gram-negative pathogens. However, there is discrepancy regarding the amikacin initial dosage, with some reports recently recommending ≥25 mg/kg and others the conventional dosage (15-20 mg/kg). Hence, we evaluated the optimal initial dosing regimen of amikacin. Pharmacokinetic (PK) parameters were estimated using a population PK analysis. The pharmacodynamic (PD) target was a ratio of ≥8 between the concentration achieved 1 h after beginning the infusion (C peak) and the minimal inhibitory concentration (MIC) of the liable bacteria. Based on the population PK parameters, we simulated individual C peak for several dosing regimens by Monte Carlo method and analyzed the C peak/MIC ratio for MICs from 0.5 to 32 µg/mL. This study included 35 infected patients (25 males), with a median (range) age and body weight of 70 (15-95) years and 49.5 (32.5-78) kg, respectively. A two-compartment model was used, and total body clearance (CL) significantly correlated with creatinine clearance, and volume of distribution (V d) with body weight. Regarding the probability to achieve a C peak/MIC of ≥8, the 15 mg/kg regimen was sufficient to achieve the PK/PD target in ≥90% of patients for a MIC of 4 µg/mL or less. The cumulative fraction of response in Pseudomonas aeruginosa was that 76% of patients achieved a C peak/MIC of 8 with the amikacin dosage of 15 mg/kg/day. We suggest that the 15-mg/kg once-daily dosage of amikacin be recommended as the initial dosage. As its maintenance dosage, the 15 mg/kg/day amikacin dosage is needed for a MIC of ≤4 µg/mL, and amikacin monotherapy for a MIC of ≥8 µg/mL should be avoided.

Assessment of optimal initial dosing regimen with vancomycin pharmacokinetics model in very low birth weight neonates.

INTRODUCTION: Pharmacokinetic of vancomycin in very low birth weight neonates showed big variety, and limited data were available due to very minor population. These facts make it difficult to adjust its optimal initial dosage. Therefore, this study was to develop optimal dosing regimen of vancomycin in very low birth weight neonates. METHODS: Between 2010 and 2015, low birth weight neonates (≤1500 g) were included in a population pharmacokinetics analysis. Based on the pharmacokinetic parameters we estimated, we simulated individual blood concentrations of vancomycin and evaluated the probability of its pharmacokinetics/pharmacodynamics (PK/PD) target attainment, such as 24-h area under the concentration-time curve (AUC24)/MIC (≥400) and blood trough concentration (10-20 µg/mL), as primary measure for several dosing regimens by Monte Carlo simulation method. RESULTS: Ten patients were prescribed vancomycin and detected its blood concentrations as routine pharmacy practice to adjust the dosage. A one-compartment model was used and clearance significantly correlated with serum creatinine and the volume of infusion. In this model, vancomycin dose at 10 mg/kg three times a day (TID) was predicted to result 86.7% of neonates for an MIC of 1 µg/mL achieving AUC/MIC of ≥400 and 30.6% of the neonates for an MIC of 2 µg/mL. Moreover, the probability of reaching the target trough concentration was 70.5% for patients treated with vancomycin 10 mg/kg TID. DISCUSSION: We recommended vancomycin 10 mg/kg TID as initial dosage regimens for low birth weight neonates infected with the pathogens showed MIC of ≤1 µg/mL.