Predictive Value of Vancomycin AUC24/MIC Ratio for 30-day Mortality in Patients with Severe or Complicated Methicillin-Resistant Staphylococcus aureus Infections: A Multicenter Retrospective Study.

BACKGROUND: Although vancomycin is typically employed against methicillin-resistant Staphylococcus aureus (MRSA) infections, the optimal ratio of 24-h area under the concentration-time curve to minimum inhibitory concentration (AUC24/MIC) for severe or complicated infections lacks clear guideline recommendations. This study aimed to determine the target AUC24/MIC ratio associated with treatment outcomes of infections treated with vancomycin. METHODS: This retrospective multicenter cohort study included adult patients receiving ≥ 5 days of vancomycin for severe/complicated MRSA infections (e.g., osteoarticular, pulmonary, endocarditis, etc.) between January 2018 and December 2023. The primary outcome was 30-day mortality, with secondary outcomes including clinical success, microbiological eradication, and nephrotoxicity. Receiver operating characteristic (ROC) curve analysis was used to identify the AUC24/MIC cutoff for 30-day mortality. Multivariate regression analysis was used to determine association between AUC24/MIC and outcomes. RESULTS: This study included 82 patients. ROC identified a target AUC24/MIC of ≥ 505 for 30-day mortality. The overall 30-day mortality rate (22.0%) was significantly higher for below average AUC24/MIC cutoff (34.1%) than for above AUC24/MIC cutoff group (9.8%). Multivariate analysis confirmed AUC24/MIC of < 505 as an independent predictor (adjusted odds ratio, 5.001; 95% confidence interval, 1.335-18.75). The clinical success rate differed significantly between below- and above-cutoff groups, whereas microbiological eradication tended to favor the above-cutoff group. The nephrotoxicity rates were comparable between groups. CONCLUSIONS: In treating severe/complicated MRSA infections, vancomycin AUC24/MIC ratio ≥ 505 was independently associated with favorable 30-day mortality. Given the retrospective nature of this study, further prospective studies are essential to confirm the reliability of the target AUC24/MIC ratios.

Potential risk factors for early acute kidney injury in patients treated with vancomycin.

PURPOSE: The acute kidney injury (AKI) onset owing to vancomycin (VCM) is reported that depend on the area under the blood concentration-time curve (AUC) and occur comparison early phase (early AKI). This study aimed to investigate the occurrence of early AKI in patients treated with VCM and new indicators to avoid early AKI. METHODS: Adult patients who received VCM treatment for more than 4 days and whose trough values measured at least once on or after day 4 and serum creatinine before day 7 from the initiation of VCM administration between August 2021 and September 2022 at the Yamanashi Prefectural Central Hospital were enrolled. Early AKI (defined as AKI occurring within day 7 from VCM administration) and the association between each AUC (0-24, 24-48, 48-72, 0-48, 24-72, 0-72) were investigated. Furthermore, each AUC cut-off value for early AKI was calculated. RESULT: In total, 164 patients were enrolled; early AKI developed in 21 patients and most frequently occurred on day 4. All stratified AUC were associated with early AKI development. The AUC cut-off values were AUC0-24: 470.8 µg/mL⋅h; AUC24-48: 473.0 µg/mL⋅h; AUC48-72: 489.7 µg/mL⋅h; AUC0-48: 910.2 µg/mL⋅h; AUC24-72: 1039.2 µg/mL⋅h; and AUC0-72: 1544.0 µg/mL⋅h. CONCLUSION: The possibility of AKI development owing to the AUC accumulation of VCM was observed (accumulation toxicity). Concentration control through early-phase blood concentration measurements and a transition to AUC0-48 <910.2 µg/mL⋅h may reduce the early-phase AKI onset.

Index for the appropriate vancomycin dosing in premature neonates and infants.

BACKGROUND: In neonates, vancomycin (VCM) is used to treat Gram-positive bacterial infections. However, VCM blood concentrations are affected by gestational age, bodyweight (BW), and renal function. The initial VCM dose adjustment can therefore be difficult, and few reports have evaluated this issue. In this study, we investigated the factors determining the appropriate VCM dosing schedule in neonates, especially premature infants. METHODS: The VCM dosage and trough concentrations were retrospectively investigated from the initial treatment to maintenance therapy in neonatal intensive care unit patients who underwent therapeutic drug monitoring. We examined the average single-administration VCM dosage during maintenance therapy. We then compared the actual VCM dose with that calculated using an index comprising six items that influence the VCM daily dose (postnatal age, gestational age, BW, serum creatinine level, urine output, and lactate level). RESULTS: Twenty premature infants were included. The average BW of patients at the initial VCM administration was 975 g. During maintenance therapy, the average VCM dose was 8.4 mg/kg, and the median trough concentration was 12.4 µg/mL. When we applied the six-item index, 18 of 20 patients (90%) had concordant results between the actual VCM dosing schedule and the VCM calculated using the index. CONCLUSIONS: The average VCM dose and six-item index can facilitate the transition from the initial VCM dose to an appropriate dose in many cases and contribute to early treatment in low-birthweight infants with more variable BW, distribution volumes, and renal function. In conclusion, our six-item index may help standardize VCM administration in premature infants.

Relationship between amikacin blood concentration and ototoxicity in low birth weight infants.

Amikacin (AMK) is used as empiric therapy for severe infections such as sepsis in low birth weight (LBW) infants. AMK administered once daily (OD) in adults is reported to be therapeutically effective and prevent side effects, however, evidence on AMK administration in LBW infants is limited, with no clear indications of effectiveness. We performed therapeutic drug monitoring analysis of 20 infants treated with AMK OD for severe infections such as bacteremia. Treatment effectiveness was admitted by the patients' medical records, and side effects of renal dysfunction and ototoxicity were investigated. The mean gestational age was 30.4 ± 5 weeks and mean body weight (Bw) was 1280.2 ± 809.8 g. The mean AMK dose was 14.1 ± 2.6 mg/kg and mean administration period was 10.1 ± 4.1 days. Blood concentration was measured 6.3 ± 2.3 days after AMK administration; mean peak and trough concentrations were 29.1 ± 7.5 µg/mL and 7.6 ± 6.9 µg/mL, respectively. Additionally, therapeutic effect was observed in all patients, and no significant change in serum creatinine (CRE) concentration (a marker of renal dysfunction) was observed, suggesting no renal dysfunction. Ototoxicity was observed in 4 patients, 3 of whom had trough concentrations ≥10 µg/mL. When we categorized patients into two groups using a trough cut-off value of 10 µg/mL, no difference in AMK dose was observed. However, there were significant differences in peak concentration, Bw, volume of distribution and CRE. Our findings suggest AMK trough concentration ≥10 µg/mL significantly affects ototoxicity in neonates.

Evaluation of nephrotoxicity and ototoxicity following amikacin administration once daily or every 48 hours in neonates.

The purpose of this study was to evaluate the effects of once daily (OD) or every 48 hours (every-48-h) administration of amikacin (AMK) on renal function and ototoxicity in neonates. We investigated the frequency of nephrotoxicity and ototoxicity in neonates who received AMK OD or every-48-h from April 2015 to March 2021 and underwent dose evaluation by therapeutic drug monitoring (TDM). In addition, the relationships among birth weight, gestational age, AMK peak and trough values, total duration of AMK administration, and total AMK dose were examined separately for nephrotoxicity and ototoxicity. AMK was administered OD in 38 patients and every-48-h in 62 patients. Nephrotoxicity was observed in 8 patients on OD versus 36 patients on every-48-h administration (P < .001), and ototoxicity was observed in 2 patients on OD versus 12 patients on every-48-h administration (P = .192). For nephrotoxicity, only the trough value was relevant (P = .007). In terms of ototoxicity, there were no influencing factors. The risk of nephrotoxicity was higher with every-48-h AMK administration than with OD AMK administration, with nephrotoxicity depending on the trough value. However, compared with OD, the every-48-h group had lower body weight and possibly poorer original renal function. In addition, ototoxicity did not differ by administration method. Based on these results, every-48-h administration of AMK can be used as safely as OD by performing TDM and preventing high concentrations.

Development of sarpogrelate external preparation for intractable pain control. I. Pre-formulation study on application of modified beta-cyclodextrins.

To optimize the formulation of in-hospital sarpogrelate (SPG) preparation for external use, various cyclodextrins (CDs) were investigated for their ability to improve the aqueous solubility and chemical stability of SPG. Although hydrolysis of SPG was markedly accelerated at above pH 7.0 in aqueous solution, the addition of modified beta-CD resulted in suppressed SPG hydrolysis. Addition of sulfobutylether-beta-CD (SBE-beta-CD, Captisol had the most significant stabilization effect. Phase solubility diagram and (1)H-NMR analyses indicated that dimethyl-beta-CD and SBE-beta-CD formed significantly stable inclusion complexes with SPG in aqueous solution, thereby contributing to both the increased solubility and chemical stabilization of SPG. In terms of the clinical safety of CD derivatives, SBE-beta-CD was determined to be the most suitable solubilizing agent for external SPG preparation.

[Evidence-based quality management of clinical formulations: determination of expiration date of powdered medicine prepared by grinding tablets].

Beraprost sodium (BPS) is often used for pediatric patients with pulmonary hypertension. The purpose of this study was to determine the expiration date of the powdered medicine prepared by grinding tablets. In the present study, the hygroscopicity and stability of the beraprost tablet (DORNER tablet), ground Dorner tablet and powder formulation (Dorner powder) consisting of the ground DORNER tablet and lactose (EFC lactose) were investigated after storage at various relative humidities (RHs) and light exposures. While the DORNER tablets and ground DORNER tablets were found to adsorb significant amounts of water vapor at an RHs of greater than 51.0%, Dorner powder scarcely adsorbed water. The stability of BPS in the Dorner powder decreased after storage under 3000 lux for 90 days. From these results, the expiration date and storage conditions of Dorner powder were determined to "90 days without exposure to light." We also investigated the stability of BPS in solutions of various pH values on the assumption that Dorner powder may be given to pediatric patients after dissolving in soft drinks. Because BPS degraded significantly below pH 2, pharmacists should alert patients not to take Dorner powder with acidic soft drinks.

A comparison of three different concentrations of ropivacaine with fentanyl for patient-controlled epidural analgesia.

BACKGROUND: The optimal concentration of ropivacaine in combination with fentanyl for patient-controlled epidural analgesia focusing on preservation of bowel function, analgesia, and motor function remains unclear. METHODS: Three hundred-twelve women scheduled to undergo gynecologic lower abdominal surgery, were randomly allocated to receive ropivacaine 0.05, 0.075, or 0.1% in combination with fentanyl 4 mug/mL and droperidol 25 microg/mL. The settings of patient-controlled epidural analgesia were as follows: initial loading volume 5 mL, background infusion 2 mL/h during night-time, no background infusion during daytime, bolus volume 2 mL, and lockout interval 10 min. Bowel function was evaluated by the first passage of flatus and feces. Pain was assessed with a visual analog scale, and motor function was examined by modified Bromage scale. Data were collected in the evening on the day of surgery, in the morning and in the evening on the first postoperative day, and in the morning on the second postoperative day. RESULTS: Gastrointestinal motility was not different among the three groups. All three solutions produced equivalent analgesia and no motor blockade. CONCLUSION: We conclude that ropivacaine 0.05% is sufficient to preserve gastrointestinal motility, and provides excellent postoperative pain relief without motor blockade.

Formulation study of intravesical oxybutynin instillation solution with enhanced retention in bladder.

A formulation study of intravesical oxybutynin (OB) preparations was carried out in order to improve the effectiveness in intravesical instillation therapy for spastic neurogenetic bladder. Sodium hyaluronate (HYA) was introduced to enhance the muco-adhesiveness of the instillation preparation, and the physicochemical properties of the OB formulation were evaluated in comparison with a conventional formulation containing hydroxypropylcellulose (HPC). The viscous properties and in vitro adhesiveness increased with the amount of the polymeric additives, and retention properties of OB in rabbit bladder were comparable after addition of 0.4% HYA and 1.0% HPC. HYA was able to enhance the intravesical retention properties of OB instillation solution to a lesser degree than HPC, it seemed to be a useful additive in the OB instillation due to its safety and mucosal-protective effect.