Gentamicin Dosage Intervals In Neonates: Longer Dosage Interval - Less Toxicity

Objectives: The aim of this study was to determine the incidence of toxic trough serum gentamicin levels in neonates in the first week of life, with different dosage intervals. Methods: This was a retrospective study of neonates born between 01.07.95 and 31.12.95, who received gentamicin. Data were collected on birth weight, gestation, gentamicin dose, the trough level of gentamicin, serum creatinine and urine output. A trough serum gentamicin level of greater than or equal to 1.5 mg/L was considered toxic. Results: One hundred and seventy infants met the study criteria. All 21 infants in group one (2429 weeks) received gentamicin with a dosage interval of 24 h. Sixteen (76%) infants had toxic trough serum gentamicin levels. In group two (3034 weeks) 8 infants had gentamicin q12hly and all (100%) had toxic trough serum gentamicin levels. Fourteen infants had gentamicin every 18 h and 13 (93%) had toxic trough serum gentamicin levels. Sixty-one infants had gentamicin q24hly and 25 (41%) had toxic trough serum gentamicin levels. The differences in proportions with toxic levels were statistically significant. In group three (greater than or equal to 35 weeks) 29 infants had gentamicin q12hly and 25 (86%) had toxic trough serum gentamicin levels. Six infants had gentamicin every 18 h and 2 (33%) had toxic trough serum gentamicin levels. Thirty-one infants had gentamicin q24hly and 4 (13%) had toxic trough serum gentamicin levels. The differences in proportions comparing infants having gentamicin q12hly with those having it q24hly were statistically significant. Conclusions: A starting gentamicin dosage interval of 12 h in infants of any gestational age, or a starting dosage interval of 24 h for infants of less than 30 weeks gestational age, leads to most having toxic trough serum gentamicin levels. In infants of 30 weeks gestational age or greater, most have safe non-toxic trough serum gentamicin levels if started on a dosage interval of 24 h

Pharmacokinetics and Pharmacodynamics of Antibacterials, Antifungals, and Antivirals Used Most Frequently in Neonates and Infants

Antimicrobials and antivirals are widely used in young infants and neonates. These patients have historically been largely excluded from clinical trials and, as a consequence, the pharmacokinetics and pharmacodynamics of commonly used antibacterials, antifungals, and antivirals are incompletely understood in this population. This review summarizes the current literature specific to neonates and infants regarding pharmacokinetic parameters and changes in neonatal development that affect antimicrobial and antiviral pharmacodynamics. Specific drug classes addressed include aminoglycosides, aminopenicillins, cephalosporins, glycopeptides, azole antifungals, echinocandins, polyenes, and guanosine analogs. Within each drug class, the pharmacodynamics, pharmacokinetics, and clinical implications and future directions for prototypical agents are discussed. β-Lactam antibacterial activity is maximized when the plasma concentration exceeds the minimum inhibitory concentration for a prolonged period, suggesting that more frequent dosing may optimize β-lactam therapy. Aminoglycosides are typically administered at longer intervals with larger doses in order to maximize exposure (i.e., area under the plasma concentration–time curve) with gestational age and weight strongly influencing the pharmacokinetic profile. Nonetheless, safety concerns necessitate therapeutic drug monitoring across the entire neonatal and young infant spectrum. Vancomycin, representing the glycopeptide class of antibacterials, has a long history of clinical utility, yet there is still uncertainty about the optimal pharmacodynamic index in neonates and young infants. The high degree of pharmacokinetic variability in this population makes therapeutic drug monitoring essential to ensure adequate therapeutic exposure. Among neonates treated with the triazole agent fluconazole, it has been speculated that loading doses may improve pharmacodynamic target attainment rates. The use of voriconazole necessitates therapeutic drug monitoring and dose adjustments for patients with hepatic dysfunction. Neonates treated with lipid-based formulations of the polyene amphotericin B may be at an increased risk of death, such that alternative antifungal agents should be considered for neonates with invasive fungal infections. Alternative antifungal agents such as micafungin and caspofungin also exhibit unique pharmacokinetic considerations in this population. Neonates rapidly eliminate micafungin and require nearly three times the normal adult dose to achieve comparable levels of systemic exposure. Conversely, peak caspofungin concentrations have been reported to be similar among neonates and adults. However, both of these drugs feature favorable safety profiles. Recent studies with acyclovir have suggested that current dosing regimens may not result in therapeutic central nervous system concentrations and more frequent dosing may be required for neonates at later postmenstrual ages. Though ganciclovir and valganciclovir demonstrate excellent activity against cytomegalovirus, they are associated with significant neutropenia. In summary, many pharmacokinetic and pharmacodynamic studies have been conducted in this vulnerable population; however, there are also substantial gaps in our knowledge that require further investigation. These studies will be invaluable in determining optimal neonatal dosing regimens that have the potential to improve clinical outcomes and decrease adverse effects associated with antimicrobial and antiviral treatments