Vancomycin In Neonates Research Articles

Pharmacokinetics of vancomycin in neonates admitted to the neonatology unit at the Jordan University Hospital

Vancomycin is used in neonatal intensive care units to treat nosocomial infections caused by methicillin-resistant Staphylococcus aureus (MRSA) or coagulase-negative staphylococci. Current dosing regimens are not adequate, producing trough concentrations below the target range. 151 neonates who received vancomycin and had vancomycin peak and trough concentration measurements as part of regular therapeutic drug monitoring were utilized. The patients were divided into three groups according to gestational age; less than 28 weeks, 28 to less than 34 weeks and 34 weeks to term. Neonates were given vancomycin doses as per guidelines. The pharmacokinetic parameters, elimination rate constant (K), elimination half-life (t1/2), volume of distribution (VD) and clearance (CL), were calculated. Peak vancomycin concentrations ranged from 9.4 to 52.8 mg/l, while troughs ranged from 0.0 to 16.6 mg/l. One third of the trough concentrations were below 5 mg/l and are thus, subtherapeutic. There were no statistically significant differences between the three groups in regard to elimination rate constant and half-life. However, there was a statistically significant difference in volume of distribution between the three groups (p < 0.05), and in clearance between the first group and the other two (p < 0.05), using Kruskal-Wallis statistical test. The empirical dosing method used was inadequate in one third of patients. Individualization of vancomycin dosing in the neonatal critical care unit at The Jordan University Hospital seems necessary.

Population pharmacokinetic analysis of vancomycin in neonates. A new proposal of initial dosage guideline

To determine the population pharmacokinetic parameters of vancomycin in neonatal patients with a wide range of gestational age and birth weight, and subsequently to design an initial dosing schedule for vancomycin in neonates. Using nonlinear mixed-effects modelling (NONMEM VI), the pharmacokinetics of vancomycin were investigated in 70 neonates with postmenstrual age and body weight ranging 25.1-48.1 weeks and 0.7-3.7kg, respectively. A one-compartment linear disposition model with zero order input and first-order elimination was used to describe the data. Nine demographic characteristics and 21 co-administered drugs were evaluated as covariates of clearance (CL) and distribution volume (V(d) ) of vancomycin. Weight-normalized clearance of vancomycin was influenced by postmenstrual age (PMA) and co-administration of amoxicillin-clavulanic acid. Weight-normalized volume of distribution was influenced by co-administration of spironolactone. CL and V(d) of the typical individual in this study population (PMA = 34.6 weeks, weight = 1.7kg) were estimated to be 0.066lh(-1) kg(-1) (95% CI 0.059, 0.073lh(-1) kg(-1) ) and 0.572lkg(-1) (95% CI 0.505, 0.639lkg(-1) ), respectively. This model was used to predict a priori serum vancomycin concentrations in a validation group (n= 41), which were compared with observed concentrations to determine the predictive performance of the model. The 95% confidence interval of mean prediction error included zero for both peak and trough vancomycin concentrations. Postmenstrual age, co-administration of amoxicillin-clavulanic acid and spironolactone have a significant effect on the weight-normalized CL and V(d) . An initial dosage guideline for vancomycin is proposed for preterm and full-term neonates, whereas the population pharmacokinetic model can be used for dosage individualization of vancomycin.

Diseño y validación de un esquema de dosificación de vancomicina en neonatos prematuros

Inappropriate use of vancomycin contributes to the development of resistant bacteria and jeopardizes the safety and effectiveness of treatment. The aim of this article was to design and validate an empirical dosing algorithm for vancomycin in premature neonates according to their population-based pharmacokinetic characteristics. We performed a retrospective analysis of 129 serum samples from a cohort of 53 neonates. Homogeneous population groups were identified both from their individual pharmacokinetic parameters and from their biometric characteristics. The design of the dosing algorithm was based on simulation of the serum vancomycin concentration that would be reached with several different doses. The algorithm was validated in another cohort of 30 neonates and 108 serum samples. Introduction of the algorithm significantly increased the percentage initial values obtained with correct minimum and maximum concentrations in the first monitoring round (p<0.05). The mean number of serum samples obtained per patient for treatment monitoring was significantly reduced (3.6+/-2 vs. 4.9+/-3). The implantation of the dosing algorithm for vancomycin in premature neonates increased the efficiency of treatment, reduced monitoring requirements, and optimized serum vancomycin concentrations from the start of treatment.

Vancomycin: pharmacokinetics and administration regimens in neonates.

This review describes the use of vancomycin in neonates over the last three decades. Given the relation of late-onset neonatal septicaemia to outcome and the increase in coagulase-negative staphylococcal infection as causative organism, vancomycin remains an important antibacterial in the neonatal intensive care unit. The pharmacokinetic behaviour of vancomycin in neonates can be adequately described by a one- or two-compartment model and is mainly determined by postconceptional age and renal function. In neonates, a patent ductus arteriosus as well as treatment with indomethacin or extracorporeal membrane oxygenation (ECMO) leads to an increase in volume of distribution and a decrease in clearance. Microbiological studies in vitro have shown that an increase in vancomycin concentrations above the minimum inhibitory concentration does not result in more effective killing. The microbiological and clinical efficacy of vancomycin in neonates has only been studied explicitly in a restricted number of patients. There are no definitive data relating serum concentrations to effect in this patient group. Vancomycin-related nephrotoxicity and ototoxicity in neonates is rare, and no clear relation to serum concentrations has been demonstrated. Based on the pharmacokinetic profile of vancomycin in neonates, several administration regimens have been constructed. Recent guidelines have suggested that dosage can be independent of gestational age or postconceptional age in neonates without renal failure. In patients with renal failure, therapy can be adequately tailored by using a regimen based on serum creatinine. The usefulness of routine monitoring of peak serum concentrations is doubtful based on the current literature. Recent research demonstrates a shift towards taking only routine trough serum concentrations in order to optimise efficacy. Patients with renal failure and other special subpopulations, such as patients exposed to ECMO or indomethacin, need to be monitored more closely.

Aminoglycoside and vancomycin serum concentration monitoring and mortality due to neonatal sepsis in Saudi Arabia.

To assess the effectiveness of monitoring of serum concentration of aminoglycosides in neonates. A retrospective evaluation of serum concentration monitoring of aminoglycosides (gentamicin and amikacin) and vancomycin in neonates treated for sepsis in a maternity and children hospital in Jeddah, Saudi Arabia, over the period 1998-2000. The total number of requests for monitoring increased sixfold in 1999 and 12-fold in 2000 relative to 1998. For aminoglycosides, the incidence of both subtherapeutic peak and toxic trough serum levels decreased significantly (P < 0.05) in 1999 and 2000 compared with 1998. Furthermore, the rate of neonatal mortality caused by sepsis showed reduction in both 1999 (34%) and 2000 (35%) in comparison with 1998 (45%). Vancomycin trough (effective) concentration monitoring revealed no change in the incidence (30%) of levels at subtherapeutic values (<5.0 microg/mL) between the compared years. Furthermore, the rate of toxic levels (>10 microg/mL) increased in both 1999 (31%) and 2000 (39%) relative to 1998 (25%). Therapeutic drug monitoring of vancomycin needs re-evaluation in the hospital to explain why existing methods are ineffective.

Pharmacology Review

Linezolid is an oxazolidinone antibiotic recently approved for treatment of infections due to antibiotic-resistant strains of Enterococcus faecium , Staphylococcus aureus, and Streptococcus pneumoniae. Because infections with these organisms, particularly vancomycin-resistant E faecium (VREF) and methicillin-resistant S aureus (MRSA), are becoming more common in critically ill neonates, linezolid is likely to play an increasingly important role in the antibiotic treatment of neonates who have antibiotic-resistant gram-positive infections. ### Mechanism of Action Oxazolidinone antibiotics, including linezolid, inhibit bacterial protein translation through a unique mechanism. Linezolid binds to the 23S subunit of the bacterial 50S ribosome. In doing so, the antibiotic blocks formation of the 70S translation initiation complex. Not surprisingly, nonclinical strains that have 23S rRNA mutations have shown linezolid resistance in vitro. ### Spectrum of Action Organisms against which linezolid has proven antibacterial efficacy include: E faecium (vancomycin-resistant strains only), S aureus (including methicillin-resistant strains), S agalactiae , S pneumoniae, and S pyogenes. Linezolid also shows in vitro activity against E faecalis (including vancomycin-resistant strains), E faecium (vancomycin-susceptible strains), S epidermidis (including methicillin-resistant strains), S haemolyticus , S pneumonia (penicillin-resistant strains), viridans-group streptococci, and Pasteurella multocida. In general, linezolid is bacteriostatic for staphylococci and enterococci, but is bactericidal for streptococci. Linezolid has activity against methicillin-sensitive and -resistant strains of S aureus and reportedly is active even against glycopeptide-intermediate and -resistant S aureus strains. ### Absorption Linezolid is administered either intravenously or orally. The intravenous preparation contains 2 mg/mL linezolid in an isotonic citrate buffer; the oral suspension contains 20 mg/mL linezolid. The oral bioavailability of linezolid suspension in older children and adults is 100% and is not altered by food. Neither preparation contains alcohol. No data on oral absorption in neonates are available. ### Distribution Linezolid distributes to well-perfused tissues and has low plasma protein binding (approximately 31%). Studies have shown that linezolid penetrates into osteoarticular tissues well, exceeding the minimum inhibitory …

Newborn hearing screening: Tobramycin and vancomycin are not risk factors for hearing loss

Objective To investigate the chance of detecting hearing loss with neonatal hearing screening in relation to exposure to tobramycin and vancomycin. Study design Automated auditory brainstem response (A-ABR) hearing screening was performed in all neonates with at least one risk factor. Data on drug administration were abstracted from patient files. Exposure to these drugs was related to the result of hearing screening. In patients failing hearing screening, exposure to ototoxic medication was assessed in the light of other risk factors for hearing loss. Results Six hundred twenty-five patients were analyzed; 45 neonates failed hearing screening. Tobramycin, vancomycin, and furosemide were used in 508, 130, and 174 patients, respectively. Exposure to vancomycin, tobramycin, or furosemide or a combination, defined in terms of treatment duration, total dose, or serum concentrations of antibiotics, was not related to failure to pass A-ABR screening. Ototoxic medication was not the most probable risk factor in any of the patients with serum concentrations outside the therapeutic range. Conclusions Routine therapeutic drug monitoring of vancomycin and tobramycin in neonates for ototoxicity reasons is not helpful in detecting patients at risk for clinically important hearing loss in the 2- to 4-kHz range. A longer period of audiometric follow-up is needed to determine any long-term effects. (J Pediatr 2003;142:41-6 )

Pharmacokinetics of vancomycin in (pre)term neonates and influence of covariates

In order to optimize the dosage regimen of vancomycin in neonates, we investigated the population pharmacokinetics and the influence of covariates on the individual pharmacokinetic parameters. Data from 105 preterm and term neonates were analyzed retrospectively. Their Post Conceptional Age (PCA) ranged from 26.5 to 44.1 weeks. Post Natal Age (PNA) was 13.7 (8.2) (mean (s.d.), range: 4–54 days. Plasma vancomycin trough and peak concentration pairs were routinely obtained around the second dose and on several days thereafter (mean 5.8 concentrations/infant). Routine gentamicin drug monitoring, immediately preceding the vancomycin course, was available in 65 infants (mean 4 concentrations/infant). Both population and individual pharmacokinetic parameters of vancomycin were calculated according to a one-compartment open model with a non-parametric expectation maximization algorithm (NPEM2, USCPACK 10.7; University SC, USA). Calculations were also performed with an iterative Bayesian fitting procedure and maximum a posteriori Bayesian fitting (MW\PHARM 3.50, Mediware, The Netherlands). The influence of several demographic and clinical covariates was calculated using stepwise multiple regression analysis with SPSS 10.0 software (Chicago, IL, USA). Recent literature indicates that serum creatinine in the first 2 weeks of life does not reflect glomerular filtration rate [1]. Therefore we also calculated the correlation between Kel gentamicin and Kel vancomycin. Three subgroups were defined: < 30, ≥ 30 and < 37, and ≥ 37 weeks’ PCA. Their population parameters (median + mean DF50+DF95) are reported in the same order: Kel (h−1): 0.0889 (0.0229), 0.1090 (0.0249), 0.1634 (0.0458) and V/W (lkg−1): 0.5487 (0.1362), 0.4950 (0.1368), 0.4229 (0.0914). Results obtained with NPEM2 and MW/PHARM were almost identical. A significant (P < 0.001) correlation was found between Kel of gentamicin and vancomycin (r = 0.579) and between serum creatinine and Kel of vancomycin (r = −0.563). Stepwise multiple linear regression analysis yielded the following statistically significant equations: A significant correlation was demonstrated between vancomycin elimination rate and serum creatinine concentrations. The correlation with gentamicin kinetics could be used in practice if plasma creatinine concentrations are not available or biased. The predictive value of the observed correlations has to be validated prospectively in clinical practice.

Vancomycin and gentamicin in neonates: hindsight, current controversies, and forethought.

The use of both vancomycin and gentamicin in the treatment of suspected or documented neonatal infections, while routine, is a challenge for bedside and advanced practice nurses caring for neonates in intensive care units. A review of the background information surrounding neonatal infections as well as the history, intended use, and the pharmacokinetic and pharmacodynamic properties of vancomycin and gentamicin is presented with the goal of aiding in proper treatment with these two medications. Specific attention is given to doses in special situations, means of drug monitoring, strategies for avoiding antibiotic resistance, alternative medication choices, and areas for future investigation.

Pharmacokinetics and dose requirements of vancomycin in neonates

AIMSTo design and evaluate dosing guidelines for vancomycin based on data collected during routine use of the drug.METHODSFollowing the observation that 66% of neonatal vancomycin trough concentrations were outside the...

Pharmacokinetics and administration regimens of vancomycin in neonates, infants and children.

The increased use of vancomycin in neonatal and paediatric patients has prompted numerous pharmacokinetic studies and the development of many empirical administration methods. The majority of dosage guidelines use the relationship between pharmacokinetic parameters and patient variables such as chronological age, bodyweight, and/or measures of renal function. Currently, those dosage guidelines which are based upon postconceptional age and bodyweight seem to provide the best options for empirical administration in neonates and infants. In addition, serum creatinine may prove to be a useful guide to the empirical administration of vancomycin in neonates older than 7 to 14 days. Several investigators have reported the individualisation of dosage regimens based on pharmacokinetic-based administration methods. The most common techniques employed have been Sawchuk-Zaske method and Bayesian forecasting. However, only a limited number of studies have evaluated either empirical administration or individualised administration techniques in patient populations outside those of the original reports; this makes choosing between the methods difficult. Pharmacokinetic data and administration recommendations have gradually become available in special paediatric patient populations. The majority of studies have focused on patients requiring cardiopulmonary bypass surgery or with burns, cancer or central nervous system infections. However, a limited amount of information is available regarding vancomycin disposition in children older than 1 year of age with and without end-stage renal failure. The monitoring of serum vancomycin concentrations may be useful in selected neonatal and paediatric patient populations, especially where large interpatient variability occurs and administration guidelines are not clearly established. Similar to the literature on adults, the lack of conclusive evidence concerning the relationship between serum vancomycin concentrations and therapeutic responses leaves this topic open to debate.

Vancomycin pharmacokinetics and dosing in premature neonates.

We prospectively studied the pharmacokinetic parameters of vancomycin in premature neonates given vancomycin according to a dosage protocol developed in our neonatal unit. Study infants were administered vancomycin according to four postconceptional age (PCA) groups: (0) 18 mg/kg every 36 h for PCA < 27 weeks; (I) 16 mg/kg every 24 h for PCA 27-30 weeks; (II) 18 mg/kg every 18 h for PCA 31-36 weeks; and (III) 15 mg/kg every 12 h for PCA > or = 37 weeks. Pharmacokinetic parameters were calculated from peak and trough serum vancomycin concentrations at steady state. Results in 44 infants (PCA, 27-44 weeks) showed that our dosage regimen achieved target peak serum vancomycin concentrations in 64% of neonates in Groups I-III, although it tended to undershoot the target trough concentrations. Volume of distribution (Vd), normalized for body weight, remained constant throughout the PCA range, with a mean value of 0.56 L/kg, whereas absolute clearance (r = 0.81) and normalized clearance (r = 0.48) increased with PCA (p < 0.005). The increase in clearance with PCA is associated with a greater elimination rate constant and shorter half-life. Vancomycin therapy can be initiated in a standard fashion according to our protocol or by individualizing the dosage regimen based on a Vd of 0.56 L/kg and clearance estimated from the infant's body weight and PCA groups.

Population Pharmacokinetics of Vancomycin in Neonates

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