Study Objective. To evaluate the impact of a hospitalwide increase in the recommended vancomycin starting dose from 45 to 60 mg/kg/day on initial vancomycin trough concentrations in children ...suspected of having an invasive methicillin‐resistant Staphylococcus aureus (MRSA) infection.
Design. Retrospective medical record review.
Setting. Dedicated children's hospital located in a tertiary care, academic medical center.
Patients. A total of 182 children aged 1 month‐12 years with normal renal function who had suspected MRSA infections treated with vancomycin during two different starting dose recommendation periods: 45 mg/kg/day divided every 8 hours during July 2006‐June 2007 (low‐dose group 88 children) and 60 mg/kg/day divided every 6 hours during July 2008‐June 2009 (high‐dose group 94 children).
Measurement and Main Results. Data on patient demographics, vancomycin doses, and initial vancomycin trough concentrations were collected. No significant demographic differences were noted between patients in the low‐dose and high‐dose groups. The mean ± SD initial vancomycin trough level increased from 7 ± 5 μg/ml in the low‐dose group to 9 ± 5 μg/ml in the high‐dose group (p<0.001). The percentage of patients with an initial trough level less than 5 μg/ml declined from 38% (33/88 children) in the low‐dose group to 17% (16/94 children) in the high‐dose group (p<0.001), whereas the percentage of patients with an initial trough concentration in the potentially adverse range (> 20 μg/ml) did not change between the two groups (2% vs 2%, p=0.9). Less than 14% (13/94 children) achieved a trough level in the range of 15–20 μg/ml in the high‐dose group.
Conclusion. An increase in the recommended vancomycin starting dose to 60 mg/kg/day decreased the likelihood of an initial low vancomycin trough level (< 5 μg/ml), with no increase in the proportion of patients with trough levels in a potentially toxic range. The 60‐mg/kg/day dose did not consistently achieve a vancomycin trough of 15–20 μg/ml, a goal suggested by some experts for adults. Comparative effectiveness studies are needed to directly evaluate vancomycin dosing regimens and clinical outcomes for children with invasive MRSA infections.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Abstract Background: Due to the emergence of community-associated strains, the prevalence of invasive methicillin-resistant Staphylococcus aureus (MRSA) infections has increased substantially in ...pediatric patients. A vancomycin AUC0–24 /MIC index >400 best predicts treatment outcomes for invasive MRSA infection in adults. Data on whether recommended vancomycin doses in children achieve this break point are lacking. Objective: This study aimed to assess the likelihood that currently recommended vancomycin doses in children achieve AUC0–24 /MIC >400. Methods: Vancomycin AUC0–24 /MIC predictions were conducted across a range of dosages (40–70 mg/kg/d) using a Monte Carlo simulation (n = 5000). AUC0–24 was calculated as daily dose divided by vancomycin clearance, and daily dose was fixed for a given simulation. Three literature-reported estimates in children were used to define vancomycin clearance and its variance. For the MIC distribution of MRSA isolates, susceptibility data were obtained from the University of California, San Francisco Children's Hospital, San Francisco, California (n = 180; 40% ≤0.5 mg/L; 59% = 1 mg/L; and 1% = 2 mg/L). Results: Using the recommended empiric dosage of 40 mg/kg/d, 58% to 66% of children were predicted to achieve AUC0–24 /MIC >400. Increasing the vancomycin dosage to 60 mg/kg/d substantially increased the likelihood (88%–98%) of achieving this pharmacodynamic target. On sensitivity analysis, a dosage of 40 mg/kg/d was more strongly influenced by small changes in MIC compared with 60 mg/kg/d. Conclusions: Recommended empiric vancomycin dosing in children (40 mg/kg/d) was not predicted to consistently achieve the pharmacodynamic target of AUC0–24 /MIC >400 for invasive MRSA infections. A vancomycin dosage of 60 mg/kg/d was predicted to optimize achievement of this target in children.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Previous studies have demonstrated that increased gastric pH from the use of acid-reducing agents, such as proton-pump inhibitors or H2-receptor antagonists, can significantly impact the absorption ...of weakly basic drugs that exhibit pH-dependent solubility. Clinically practical strategies to mitigate this interaction have not been developed. This pilot study evaluated the extent and time course of gastric reacidification after a solid oral dosage form of anhydrous betaine HCl in healthy volunteers with pharmacologically induced hypochlorhydria. Six healthy volunteers with baseline normochlorhydria (fasting gastric pH < 4) were enrolled in this single period study. Hypochlorhydria was induced via 20 mg oral rabeprazole twice daily for four days. On the fifth day, an additional 20 mg dose of oral rabeprazole was given and gastric pH was monitored continuously using the Heidelberg pH capsule. After gastric pH > 4 was confirmed for 15 min, 1500 mg of betaine HCl was given orally with 90 mL of water and gastric pH was continuously monitored for 2 h. Betaine HCl significantly lowered gastric pH by 4.5 (±0.5) units from 5.2 (±0.5) to 0.6 (±0.2) (P < 0.001) during the 30 min interval after administration. The onset of effect of betaine HCl was rapid, with a mean time to pH < 3 of 6.3 (±4.3) min. The reacidification period was temporary with a gastric pH < 3 and < 4 lasting 73 (±33) and 77 (±30) min, respectively. Betaine HCl was well tolerated by all subjects. In healthy volunteers with pharmacologically induced hypochlorhydria, betaine HCl was effective at temporarily lowering gastric pH. The rapid onset and relatively short duration of gastric pH reduction gives betaine HCl the potential to aid the absorption of orally administered weakly basic drugs that exhibit pH-dependent solubility when administered under hypochlorhydric conditions.
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IJS, KILJ, NUK, PNG, UL, UM
In this double-blind, placebo-controlled, crossover study we compared the analgesic effect of a single oral dose of 30-mg dextromethorphan and 30-mg morphine combination (MS/DM) to 30 mg morphine ...(MS) alone and either placebo or 30 mg dextromethorphan (DM) on cutaneous sensitization induced by heat/capsaicin (topical) sensitization on the forearm and the brief thermal sensitization model on the thigh in 22 healthy volunteers. Outcome measures were areas of secondary hyperalgesia to brush and von Frey hair stimulation in both sensitization models and the painfulness of acute thermal noxious stimulation on the upper arm. Compared with placebo, both MS/DM and morphine had some effect on the secondary hyperalgesia and reduced the painfulness of a noxious thermal stimulus. The analgesic effect of MS/DM was not superior to that of morphine on any outcome measure. These results differ from preclinical studies with animal experimental pain models in which DM markedly potentiated the analgesic effects of opioids, but they are in accordance with recent clinical trials for chronic pain.
Adding dextromethorphan to morphine (1:1 ratio) did not enhance analgesia on measures of experimental cutaneous sensitization and acute noxious thermal stimulation in healthy volunteers. The results differ from preclinical studies but agree with clinical trials. Human experimental models of pain and neuronal sensitization, which are responsive to oral opioids, allow efficient study of opioid combination analgesics and simplify the process for determining the optimal dose and/or dose ratio.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Current management approaches for asymptomatic neonates at risk of early onset sepsis remain controversial. Strategies based entirely on clinical observation (SCO, serial clinical observation) have ...gained consensus.
We briefly compare different strategies for managing asymptomatic newborns suggested in four high-income countries. Then this review details the existing differences in carrying out the SCO in the United Kingdom, the USA, and Italy; the experiences from the studies performed using the SCO; and open questions regarding this strategy. Advantages and limitations of SCO are also discussed. There is a need to assess which symptoms at birth are more predictive of early onset sepsis and therefore require immediate interventions versus those symptoms that can be monitored and re-evaluated.
SCO strategy may require changes in the processes of newborn care at birthing centers. Nonetheless, SCO is safe and is associated with fewer laboratory evaluations and unnecessary antibiotics. Thoughtful and thorough practices related to the care of all newborns will benefit any birthing centre. VIDEO ABSTRACT: http://links.lww.com/MOP/A40.
Vancomycin is commonly used to treat acute pulmonary exacerbations in pediatric patients with cystic fibrosis (CF) and a history of methicillin-resistant Staphylococcus aureus. Optimizing vancomycin ...exposure during therapy is essential and area under the curve (AUC)-guided dosing is now recommended. Model-informed precision dosing (MIPD) utilizing Bayesian forecasting is a powerful approach that can support AUC-guided dose individualization. The objective of the current study was to examine the impact of implementing an AUC-guided dose individualization approach supported via a MIPD clinical decision support (CDS) tool on vancomycin exposure, target attainment rate, and safety in pediatric patients with CF treated with vancomycin during clinical care.
Retrospective chart review was performed in patients with CF at a single children's hospital comparing pre- and post-implementation of a MIPD approach for vancomycin supported by a cloud-based, CDS tool integrated into the electronic health record (EHR). In the pre-MIPD period, vancomycin starting doses of 60 mg/kg/day (<13 years) or 45 mg/kg/day (≥13 years) were used. Dose adjustment was guided by therapeutic drug monitoring (TDM) with a target trough 10-20 mg/L. In the post-MIPD period, starting dose and dose-adjustment were based on the MIPD CDS tool predictions with a target 24 hour AUC (AUC
) 400-600 mg*hr/L. Exposure and target achievement rates were retrospectively calculated and compared. Rates of acute kidney injury (AKI) were also compared.
Overall, 23 patient courses were included in the pre-MIPD period and 21 patient courses in the post-MIPD period. In the post-MIPD period, an individualized MIPD starting dose resulted in 71% of patients achieving target AUC
compared to 39% in the pre-MIPD period (p<0.05). After the first TDM and dose adjustment, target AUC
achievement was also higher post-MIPD versus pre-MIPD (86% vs 57%; p<0.05). AKI rates were low and similar between periods (pre-MIPD 8.7% vs post-MIPD 9.5%; p=0.9).
An MIPD approach implemented within a cloud-based, EHR integrated CDS tool safely supported vancomycin AUC-guided dosing and resulted in high rates of target achievement.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Neonates with hypoxic-ischemic encephalopathy (HIE) frequently develop acute kidney injury (AKI). Aminophylline has been shown to reduce severe renal dysfunction in neonates after perinatal asphyxia. ...However, the effect of aminophylline on renal function in neonates undergoing hypothermia has not been studied.
A single-center, retrospective chart review of neonates cooled for moderate/severe HIE who received aminophylline for AKI was conducted to assess changes in urine output (UOP) and serum creatinine (SCr). Comparisons were also made to control neonates matched for hours of life who were cooled but unexposed to aminophylline.
Sixteen neonates cooled for HIE received aminophylline starting at 25 ± 14 h of life. Within 12 h of starting aminophylline, UOP increased by 2.6 ± 1.9 mL/kg/h. SCr declined by 0.4 ± 0.2 mg/dL in survivors over the first 4 days. When compared to control neonates, UOP increase was greater in the aminophylline group (p < 0.001). SCr declined in survivors in both groups, although baseline SCr was higher in the aminophylline group.
Aminophylline use in neonates with HIE undergoing hypothermia was associated with an increase in UOP and a decline in SCr. A randomized trial will be needed to establish a potential renal protective role of aminophylline.
The renal protective effect of aminophylline in neonates with HIE has not yet been studied in the context of therapeutic hypothermia. Aminophylline exposure in neonates cooled for HIE was associated with increased UOP and a similar decline in SCr when compared to control infants unexposed to aminophylline. Improved renal function after receiving aminophylline in this observational cohort study suggests the need for future randomized trials to establish the potential benefit of aminophylline in the HIE population undergoing hypothermia.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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