Gentamicin In Infants Research Articles

Ampicillin and Gentamicin in Infants With Suspected Sepsis

Ampicillin and Gentamicin in Infants With Suspected Sepsis

Update on Acute Bone and Joint Infections in Paediatrics: A Narrative Review on the Most Recent Evidence-Based Recommendations and Appropriate Antinfective Therapy.

Acute bone and joint infections (BJIs) in children may clinically occur as osteomyelitis (OM) or septic arthritis (SA). In clinical practice, one-third of cases present a combination of both conditions. BJIs are usually caused by the haematogenous dissemination of septic emboli carried to the terminal blood vessels of bone and joints from distant infectious processes during transient bacteraemia. Early diagnosis is the cornerstone for the successful management of BJI, but it is still a challenge for paediatricians, particularly due to its nonspecific clinical presentation and to the poor specificity of the laboratory and imaging first-line tests that are available in emergency departments. Moreover, microbiological diagnosis is often difficult to achieve with common blood cultures, and further investigations require invasive procedures. The aim of this narrative review is to provide the most recent evidence-based recommendations on appropriate antinfective therapy in BJI in children. We conducted a review of recent literature by examining the MEDLINE (Medical Literature Analysis and Retrieval System Online) database using the search engines PubMed and Google Scholar. The keywords used were “osteomyelitis”, OR “bone infection”, OR “septic arthritis”, AND “p(a)ediatric” OR “children”. When BJI diagnosis is clinically suspected or radiologically confirmed, empiric antibiotic therapy should be started as soon as possible. The choice of empiric antimicrobial therapy is based on the most likely causative pathogens according to patient age, immunisation status, underlying disease, and other clinical and epidemiological considerations, including the local prevalence of virulent pathogens, antibiotic bioavailability and bone penetration. Empiric antibiotic treatment consists of a short intravenous cycle based on anti-staphylococcal penicillin or a cephalosporin in children aged over 3 months with the addition of gentamicin in infants aged under 3 months. An oral regimen may be an option depending on the bioavailability of antibiotic chosen and clinical and laboratory data. Strict clinical and laboratory follow-up should be scheduled for the following 3–5 weeks. Further studies on the optimal therapeutic approach are needed in order to understand the best first-line regimen, the utility of biomarkers for the definition of therapy duration and treatment of complications.

Extended-interval Dosing of Gentamicin in Premature Neonates Born at 7 Days of age

PurposeExtended-interval dosing (EID) regimens of gentamicin have been validated for treating confirmed or suspected early- and late-onset sepsis in preterm infants in the first week of life. Despite the marked changes in volume of distribution and renal clearance in preterm infants after the first few days of life, few studies have validated EID regimens of gentamicin in this population. The objective of the study was to evaluate an EID regimen of gentamicin in infants born at <32 weeks’ gestational age and aged >7 days. MethodsThis observational study of an EID regimen was conducted in 39 infants. Dosing interval was based on the serum drug concentration at 22 hours after the administration of the first dose of 5 mg/kg. Gentamicin peak (5–12 µg/mL) and trough (<2 µg/mL) levels were compared to those in a historical control group of 39 infants who received traditional-interval dosing (TID) of 2.5 mg/kg of gentamicin with dosing intervals of 8, 12, or 24 hours. FindingsThere were no differences in birthweight, gestational age at birth, postmenstrual age, weight at the start of gentamicin administration, postnatal age, small for gestational age status, antenatal corticosteroid use, or postnatal indomethacin exposure between the 2 groups. In the EID group, dosing intervals were 24 hours in 30 infants, 36 hours in 6 infants, and 48 hours in 3 infants. Compared with the TID group (n = 39), the EID group had a significantly higher peak level (median, 9.0 vs 4.7 µg/mL) and a significantly lower trough level (median, 0.7 vs 1.1 µg/mL) (both, P < 0.001). On regression analysis, the postmenstrual age was correlated significantly with trough levels in the EID group. There was no adverse effect on renal function in either group. On follow-up, 1 infant in the EID group and 2 infants in the TID group had evidence of sensorineural hearing loss. ImplicationsIn infants born at <32 weeks’ gestation and >7 days of age, an EID gentamicin regimen, with a dosing interval based on a single concentration measurement at 22 hours after the administration of the first dose, achieved therapeutic peak and trough levels and performed significantly better than did a TID regimen in reaching target peak and trough levels. Larger-scale trials are needed for assessing the clinical efficacy (treatment failure/success) of these regimens.

Population pharmacokinetics of gentamicin and dosing optimization for infants.

The aim of this study was to characterize and validate the population pharmacokinetics of gentamicin in infants and to determine the influences of clinically relevant covariates to explain the inter- and intraindividual variabilities associated with this drug. Infants receiving intravenous gentamicin and with routine therapeutic drug monitoring were consecutively enrolled in the study. Plasma concentration and time data were retrospectively collected from 208 infants (1 to 24 months old) of the Hospital Universitario Severo Ochoa (Spain), of whom 44% were males (mean age [± standard deviation], 5.8 ± 4.8 months; mean body weight, 6.4 ± 2.2 kg). Data analysis was performed with NONMEM 7.2. One- and two-compartment open models were analyzed to estimate the gentamicin population parameters and the influences of several covariates. External validation was carried out in another population of 55 infants. The behavior of gentamicin in infants exhibits two-compartment pharmacokinetics, with total body weight being the covariate that mainly influences central volume (Vc) and clearance (CL); this parameter was also related to creatinine clearance. Both parameters are age related and different from those reported for neonatal populations. On the basis of clinical presentation and diagnosis, a once-daily dosage regimen of 7 mg/kg of body weight every 24 h is proposed for intravenous gentamicin, followed by therapeutic drug monitoring in order to avoid toxicity and ensure efficacy with minimal blood sampling. Gentamicin pharmacokinetics and disposition were accurately characterized in this pediatric population (infants), with the parameters obtained being different from those reported for neonates and children. These differences should be considered in the dosing and therapeutic monitoring of this antibiotic.

48-hour dosing of gentamicin in infants born at less than 28 weeks of gestation

48-hour dosing of gentamicin in infants born at less than 28 weeks of gestation

The effect of postnatal age on gentamicin pharmacokinetics in neonates.

To determine if gentamicin serum concentrations obtained from newborns on day 2 of life versus days 3-4 yield significantly different pharmacokinetic parameter values. Retrospective chart review. Neonatal intensive care unit. Two hundred and sixty-seven infants who had peak and trough gentamicin serum concentrations determined on days 2, 3, or 4 of life. Determination of peak and trough serum gentamicin concentrations on days 2, 3, or 4 of life. The elimination rate constant, serum half-life, volume of distribution, and clearance of gentamicin were calculated using a one-compartment pharmacokinetic model. Gestational age, birthweight, gentamicin dosage, peak and trough gentamicin concentrations, and hours after birth at which serum concentrations were drawn were recorded for all infants. Infants were stratified into three groups based on gestational age: 28 weeks or younger, older than 28 weeks but younger than 37 weeks, and 37 weeks or older. Birthweight and calculated pharmacokinetic parameters were compared by 2-tailed Student t test to determine if significant differences existed between pharmacokinetics parameters determined on day 2 of life versus days 3 or 4 within each of the gestational age groups. These analyses revealed only one significant difference between parameters assessed on day 2 versus days 3 or 4: at day 2, the mean trough concentration of gentamicin in infants of gestational age between 28 and 37 weeks was 1.63 +/- 0.44 mg/L, whereas at days 3 or 4, the same parameter for patients of the same gestational age was 1.4 +/- 0.48 mg/L (p=0.005). With one exception--elevated trough concentrations in infants in the gestational age group between 28 and 37 weeks--pharmacokinetic parameters calculated using gentamicin serum concentrations determined on day 2 of life are not significantly different from those derived from gentamicin serum concentrations determined on days 3 or 4. This suggests that gentamicin serum concentrations and subsequent dosage adjustments can be determined on day 2 of life.

Once daily dosing of gentamicin in infants and children

Aminoglycosides are frequently used in children. The standard daily dosing (SDD) in infants and children is twice or three times daily depending on age. The aim of this paper is to review the current data regarding the safety and effectiveness of once daily dosing (ODD) of gentamicin in children. A Medline search was conducted for comparison studies between ODD and SDD of gentamicin in children in term of pharmacokinetic indices and toxicity. Overall 13 studies describing ODD of gentamicin in children were found suitable for this review. In most studies steady state peak serum gentamicin concentrations were significantly higher in the ODD groups. Steady state trough concentrations >2 microg/ml were documented in 5 to 55% of patients treated with the SDD as compared with 0 to 24% in the ODD groups. The mode of dosing did not affect the volume of distribution; however, the t1/2 was significantly longer in the ODD groups. ODD was found to be cost-saving. In a few studies the efficacy of ODD was similar to that of SDD. These studies suggest that ODD compared with SDD of gentamicin is theoretically more efficacious and has no higher toxicity at 48 to 96 h in neonates and at 3 to 10 days of therapy in older infants and children.

Pharmacokinetics of gentamicin in neonates on extracorporeal membrane oxygenation.

Extracorporeal membrane oxygenation (ECMO) has been used in more than 1,000 infants in 50 centers in the United States. The extracorporeal circuit contains approximately 400 ml of blood, an amount exceeding the blood volume of most full-term neonates. The effect of this additional blood volume on drug disposition is unknown. In this study, we determined the pharmacokinetic parameters of gentamicin in 10 infants on ECMO. Gentamicin concentrations were determined by a fluorescence polarization immunoassay. Pharmacokinetic parameters were determined from these concentrations by using a two-compartment model. Our study demonstrated a mean steady-state volume of distribution of 0.51 +/- 0.11 liters/kg, a figure similar to that in previous studies of full-term infants. The elimination half-life was found to be prolonged (mean, 573 +/- 263 min). The creatinine level in the plasma of the infants was found to be a statistically significant predictor of elimination half-life. Recommendations regarding initial dosing levels of gentamicin in infants on ECMO are made.

THE DISPLACEMENT OF ALBUMIN-BOUND BILIRUBIN BY GENTAMICIN

Gentamicin is extensively used in the neonatal period but preliminary evidence indicates it can cause the displacement of bilirubin from albumin (Odell, Ann. N.Y. Acad. Sci. 226: 225, 1973). Addition of gentamicin at therapeutic concentrations to model sera and human serum from jaundiced infants caused dissociation of bilirubin from alburmin similar to salicylate. This was reflected by shifts in the absorption curves to lower wave lengths and by adsorption to red cells and mitochondria. There was also a very strong correlation between the amount of displacement by salicylate and gentamicin in pre-exchange blood samples, (r=.94, p<.001 n=18). On a molar basis gentamicin is more effective than salicylate and sulfonamides in displacing bilirubin from albumin. Injection (i.p.) of gentamicin in jaundiced Gunn rats at doses of 3, 3.5 and 6μg/kg was associated with 28, 38 and 52% decreases, respectively, in the serum bilirubin concentrations at 30 min and 19, 28, 35% decreases at 60 min. Animals injected with either saline, or kanamycin (7.5 and 15 μg/kg) exhibited only a 5% decrease in their serum bilirubins at 30 and 60 min. These results suggest that the use of gentamicin in infants with neonatal hyperbilirubinemia may increase the risk of bilirubin encephalopathy.

Clinical pharmacology of gentamicin in infants 2 to 24 months of age.

Twenty-two infants 2 to 24 months old received gentamicin sulfate intramuscularly in dosages of 1.5 to 2.5 mg/kg every eight hours for from three to ten days. Peak serum gentamicin levels following 2.0 or 2.5 mg/kg doses were equal to or greater than minimal inhibitory concentrations of most gram-negative pathogens of infancy; antibiotic levels persisted in serum for at least eight hours. Half-life values in serum were inversely related to age, and values of 2.5 hours in older infants were similar to adult values. Gentamicin concentrations in urine were 3μg to 478μg/ml and excretion of gentamicin directly correlated with creatinine clearance rates. Acute hematologic or renal toxicity was not evident. Gentamicin doses of 2.0 or 2.5 mg/kg administered every eight hours to infants up to 2 years of age are safe and adequate to treat infections caused by susceptible gram-negative enteric bacteria and<i>Pseudomonas</i>.

Clinical and laboratory evaluation of gentamicin in infants and children.

This report describes the results of extensive laboratory and clinical evaluation of gentamicin in infants and children. Of more than 4,000 strains of gramnegative bacteria, over 95% were susceptible to the antibiotic in vitro. The results of studies of the absorption, excretion, and distribution of gentamicin in different doses in subjects ranging in age from the neonatal period through adolescence are described. Sixty-nine of 76 patients with bacterial gastroenteritis responded to the drug administered orally. The therapeutic response was considered satisfactory in approximately 75% of patients with serious infections, including pyelonephritis, pneumonia, meningitis, septicemia, and others due to gram-negative bacteria. There was no evidence of serious toxicity due to gentamicin. The preliminary pharmacologic results with an experimental formulation containing 10 mg of gentamicin, intended for use in neonates and young infants, were encouraging.