Therapeutic drug monitoring of antimicrobial drugs in neonates. An opinion paper

Neonatal infections are associated with high morbidity and mortality rates. Optimal treatment of these infections requires knowledge of neonatal pharmacology and integration of neonatal developmental pharmacokinetics (PKs) of antimicrobial drugs in the design of dosing regimens for use with different gestational and postnatal ages. Population PK and pharmacodynamic models are used to personalize the use of these drugs in these fragile patients. The final step to further minimize variability in an individual patient is therapeutic drug monitoring (TDM), where the same population PK/pharmacodynamic models are used in concert with optimally drawn blood samples to further fine-tune therapy. The purpose of this article is to describe the present status and future role of model-based precision dosing and TDM of antimicrobial drugs in neonates. METHODS: PubMed was searched for clinical trials or clinical studies of TDM in neonates. RESULTS: A total of 447 articles were retrieved, of which 19 were concerned with antimicrobial drugs. Two articles (one aminoglycoside and one vancomycin) addressed the effects of TDM in neonates. We found that, in addition to aminoglycosides and vancomycin, TDM also plays a role in beta-lactam antibiotics and antifungal drugs. CONCLUSIONS: There is a growing awareness that, in addition to aminoglycosides and vancomycin, the use of beta-lactam antibiotics, such as amoxicillin and meropenem, and other classes of antimicrobial drugs, such as antifungal drugs, may benefit from TDM. However, the added value must be shown. New analytical techniques and software development may greatly support these novel developments

Separator fluid volume requirements in multi-infusion settings

INTRODUCTION. Intravenous (IV) therapy is a widely used method for the administration of medication in hospitals worldwide. ICU and surgical patients in particular often require multiple IV catheters due to incompatibility of certain drugs and the high complexity of medical therapy. This increases discomfort by painful invasive procedures, the risk of infections and costs of medication and disposable considerably. When different drugs are administered through the same lumen, it is common ICU practice to flush with a neutral fluid between the administration of two incompatible drugs in order to optimally use infusion lumens. An important constraint for delivering multiple incompatible drugs is the volume of separator fluid that is sufficient to safely separate them. OBJECTIVES. In this pilot study we investigated whether the choice of separator fluid, solvent, or administration rate affects the separator volume required in a typical ICU infusion setting. METHODS. A standard ICU IV line (2m, 2ml, 1mm internal diameter) was filled with methylene blue (40 mg/l) solution and flushed using an infusion pump with separator fluid. Independent variables were solvent for methylene blue (NaCl 0.9% vs. glucose 5%), separator fluid (NaCl 0.9% vs. glucose 5%), and administration rate (50, 100, or 200 ml/h). Samples were collected using a fraction collector until <2% of the original drug concentration remained and were analyzed using spectrophotometry. RESULTS. We did not find a significant effect of administration rate on separator fluid volume. However, NaCl/G5% (solvent/separator fluid) required significantly less separator fluid than NaCl/NaCl (3.6 ± 0.1 ml vs. 3.9 ± 0.1 ml, p <0.05). Also, G5%/G5% required significantly less separator fluid than NaCl/NaCl (3.6 ± 0.1 ml vs. 3.9 ± 0.1 ml, p <0.05). The significant decrease in required flushing volume might be due to differences in the viscosity of the solutions. However, mean differences were small and were most likely caused by human interactions with the fluid collection setup. The average required flushing volume is 3.7 ml. CONCLUSIONS. The choice of separator fluid, solvent or administration rate had no impact on the required flushing volume in the experiment. Future research should take IV line length, diameter, volume and also drug solution volumes into account in order to provide a full account of variables affecting the required separator fluid volume

Pharmacokinetic/pharmacodynamic analysis of weight- and height-scaled tobramycin dosage regimens for patients with cystic fibrosis

OBJECTIVES: To determine the outcomes of weight- and height-based tobramycin dosing regimens for patients with cystic fibrosis (CF). METHODS: A simulated dataset of 5000 patients based on 331 patients with CF was created using NONMEM. Pharmacokinetic (PK) parameters were derived for each patient from a published model using Monte Carlo simulation. The abilities of 10 and 12 mg/kg/day and 3 and 4 mg/cm/day to achieve standard and extended Cmax (20-30 and 20-40 mg/L) and AUC0-24 (80-120 and 80-150 mg·h/L) targets were evaluated. PK/pharmacodynamic (PK/PD) indices were a Cmax/MIC ratio ≥10 and an AUC0-24/MIC ratio ≥110. For these indices and a range of MICs, cumulative fractions of response (CFRs) for Pseudomonas aeruginosa were also determined. RESULTS: More patients achieved standard Cmax and AUC0-24 targets with 3 mg/cm/day (64% and 62%, respectively) than with 10 mg/kg/day (43% and 48%, respectively). AUC0-24 estimates >120 mg·h/L were more common with weight-based dosing. With higher doses, 72% achieved high target peaks with 4 mg/cm/day and 65% with 12 mg/kg/day. For the Cmax/MIC index, the maximal MIC for the target microorganism was 2 mg/L with lower doses, 2.5 mg/L with higher doses and 0.5 mg/L for AUC0-24/MIC-based regimens. The CFR for all regimens was >90% for Cmax targets and 66% to 79% for AUC0-24 targets. CONCLUSIONS: A tobramycin dose of 3 mg/cm/day rather than 10 mg/kg/day achieved similar PK/PD outcomes but dose and AUC0-24 ranges were narrower and the incidence of high AUC0-24 values was lower. Height-based doses should therefore be considered for patients with CF

Pharmacokinetics and sputum penetration of azithromycin during once weekly dosing in cystic fibrosis patients

In this study we examined pharmacokinetics, systemic exposure and sputum penetration of azithromycin (AZM) in CF patients on chronic daily AZM therapy after changing to a once weekly dosing scheme. Eight adult CF patients using AZM 500 mg/day were changed to a once weekly dose of 1000 mg during 3 months. Once per month sputum and blood samples were collected. AZM was quantified in blood plasma and polymorphonuclear neutrophils. The cumulative weekly dose was reduced with a factor of 3.5 (7x500 mg vs. 1x1000 mg weekly). This led to a reduction in area under the curve (AUC+/-S.D.) with a factor of 2.5+/-0.8 in plasma, 2.8+/-0.9 in blood, 2.2+/-1.1 in PMNNs and to a reduction in average sputum concentration with a factor of 3.0 (+/-1.5). At 1000 mg once weekly reduced but still substantial concentrations were achieved in PMNNs and in sputum. Although not significant, a tendency towards less than linear reduction was found. In order to calculate and propose an optimal dosing scheme we need to establish a relation between exposure levels and clinical efficacy

The pharmacokinetics of antibiotics in cystic fibrosis

Introduction Dosing of antibiotics in people with cystic fibrosis (CF) is challenging, due to altered pharmacokinetics, difficulty of lung tissue penetration, and increasing presence of antimicrobial resistance. Areas covered The purpose of this work is to critically review original data as well as previous reviews and guidelines on pharmacokinetics of systemic and inhaled antibiotics in CF, with the aim to propose strategies for optimization of antibacterial therapy in both children and adults with CF. Expert opinion For systemic antibiotics, absorption is comparable in CF patients and non-CF controls. The volume of distribution (Vd) of most antibiotics is similar between people with CF with normal body composition and healthy individuals. However, there are a few exceptions, like cefotiam and tobramycin. Many antibiotic class-dependent changes in drug metabolism and excretion are reported, with an increased total body clearance for ss-lactam antibiotics, aminoglycosides, fluoroquinolones, and trimethoprim. We, therefore, recommend following class-specific guidelines for CF, mostly resulting in higher dosages per kg bodyweight in CF compared to non-CF controls. Higher local antibiotic concentrations in the airways can be obtained by inhalation therapy, with which eradication of bacteria may be achieved while minimizing systemic exposure and risk of toxicity

Reducing the risk of non-sterility of aseptic handling in hospital pharmacies, part C: applying risk assessment and risk control in practice

Objectives To describe the application of the model described in part A and part B of this series of articles for risk assessment (RA) and risk control (RC) of non-sterility during aseptic handling. The model was applied in nine hospital pharmacies. Methods The starting point was an audit of each hospital pharmacy. The determined risk reduction and remaining risks were entered into a risk assessment model. The corresponding risk prioritisation numbers (RPNs) for each source of risk were calculated and these values were summed up to a cumulative RPN. Subsequently, all hospital pharmacies started an improvement programme, using the risk assessment as input. Results of aseptic process simulation (APS) and microbiological monitoring (MM) were also collected. The participants were informed about their progress of risk reduction and results of APS and MM during the study period. At the end of the study (about 4 years after the start), a final assessment was executed by using a checklist with risk reducing measures for each source of risk. Additional risk reduction and remaining risks were put in an RA and RC template and corresponding RPN values and a new cumulative RPN were determined. Results At the start of the study differences in cumulative RPN values were relatively small (from 630 to 825). At the end they were relatively great (from 230 to 725), which illustrates a different sense of urgency for reducing the risk of non-sterility. Of all the risk reducing measures, a yearly audit of all operators had the greatest impact on reducing the risk of non-sterility. Except for glove prints, there was no correlation between process improvement (lower cumulative RPN) and results of microbiological controls. Conclusion A systematic and science-based reduction of the risks of non-sterility can be done by using a checklist with risk reducing measures and an RA & RC template. Prospectively, the relevance of each risk reducing measure can be demonstrated by RPN calculations. Microbiological controls are an important part of the overall assurance of product quality. However, the results are less useful for assessing the risk of non-sterility.Clinical Pharmacy and Toxicolog