The primary focus of this small study was to compare fetal and maternal peak gentamicin concentrations and elimination between our 2 study groups. The once-daily gentamicin dosing regimen resulted in fetal serum peak drug levels that were consistently greater than 5 μg/mL and typically in the range of 7–8 μg/mL, whereas conventional dosing led to peak fetal concentrations in the range of 2–4 μg/mL. A higher peak serum drug level provides increased and more rapid in vitro antibacterial activity and longer periods of bacterial killing after the MIC has been reached. The latter phenomenon, known as the post antibiotic effect, results not only in greater antibacterial activity but also in reduced adaptive resistance.11
Studies evaluating optimal peak gentamicin concentrations on neonates are few, and recommendations for dosing in these patients are guided by extrapolated data from adult studies. Achievement of peak serum concentrations greater than 5–8 μg/mL in adults with serious infections has been associated with a lower incidence of mortality and a higher overall clinical response rate.3,4,12 Respected authorities in neonatology and pediatrics recommend aiming for the same goal in the relatively immunocompromised neonate.13–15 Five to 10% of neonates delivered to mothers with clinical chorioamnionitis have bacteremia or pneumonia.1 These fetuses are probably infected in utero, and their ultimate response to therapy might be improved by obtaining higher peak drug levels before they are delivered. Achieving the same gentamicin levels in the fetus as are targeted in the newborn infant is, in our opinion, worthy of further investigation.
As expected, peak fetal gentamicin levels were one-third that of maternal peak concentrations. Approximately 50% of the drug crosses the placenta unchanged.16 Additionally, the volume of distribution of gentamicin is larger in neonates than adults.17,18 A number of pharmacokinetic studies in neonates have demonstrated that loading doses of 5 mg/kg are required to achieve desired initial peak therapeutic concentrations of 5–10 μg/mL.17–19 According to our results, maternal loading doses of 5, or even perhaps 7, mg/kg would be necessary to achieve peak values consistently in this range.
We found 1 report in the literature that compared neonatal (rather than fetal) serum gentamicin concentrations after once-daily compared with conventional dosing regimens in the mothers.20 This group found no relationship between individual serum concentrations in the infants and the time from their mothers’ last dose. Their findings create concern regarding the fetus’ ability to clear gentamicin from the bloodstream. In contrast, we found inverse correlations between umbilical cord gentamicin concentration and time. We constructed elimination curves and estimated half-lives for each group. Fetal gentamicin clearance was not abnormally prolonged in either the high-dose or standard-dose group. The estimated half-lives in each group were consistent with published values of approximately 5 hours in newborn infants aged 0–7 days.21 These findings indicate that the term or near-term fetus is able to clear gentamicin as effectively as the term neonate.
Aminoglycoside nephrotoxicity is almost always reversible and results from accumulation and retention of the drug in the proximal tubular cells.22,23 The initial manifestation of damage is excretion of enzymes at the renal tubular brush border.24 Later, renal concentrating ability and glomerular filtration are impaired, and casts may appear in the urine.25 Ototoxicity results from progressive destruction of hair cells in the cochlea (organ of Corti)26 and vestibula (crista ampullaris).27 These histologic changes result in impaired ability of the cochlea to generate an action potential in response to sound. Once these sensory cells are lost, regeneration does not occur, resulting in degeneration of the auditory nerve and permanent hearing loss.2
Animal models have demonstrated that gentamicin uptake in the renal cortex and ear perilymph is a saturable process that is relatively unaffected by drug concentration.28 A conclusion from these studies is that prolonged moderate drug levels, rather than transient high peak serum concentrations, lead to excessive drug accumulation in the renal and cochlear systems. Studies in adults with serious infections have concluded that desirable gentamicin trough concentrations are less than 2 μg/mL.29 These levels were reached in the fetus at 8–9 hours in the once daily dosing group. Once-daily dosing potentially reduces nephrotoxicity and ototoxicity by limiting the total exposure per dosing interval and by ensuring a low concentration or drug-free period in each dosing interval to allow redistribution of the aminoglycoside out of the proximal renal tubules and perilymph where it is known to concentrate.30 Dosing intervals of 24 hours should allow sufficient time for the fetal kidney and cochlea to clear the drug. Such large intervals between doses, however, raise concern about efficacy. More study is needed to determine the optimal dosage and interval between doses.
Peak gentamicin levels in both of the groups of laboring women in our study were similar to those achieved with equivalent gentamicin doses in postpartum women with endometritis in other studies.6,7,31–34 The 90–120 minute half-life of gentamicin in our laboring subjects is shorter than the 2–3 hours that is generally described for the postpartum period6,7,31–34 and similar to what has been described during pregnancy.35 The standard MIC of 2 μg/mL in the mothers and their fetuses was reached 6–10 hours after dosage administration in the once-daily group. The postantibiotic effect in vivo after aminoglycoside administration lasts from 1–13 hours in animal models of gram-negative bacterial infection.36 This effect is extended by higher peak aminoglycoside concentrations37,38 and by concurrent administration of a cell-wall active antibiotic.39 As with our findings in the fetus, our maternal results indicate that doses higher than 5.1 mg/kg or intervals shorter than 24 hours might be preferred in pregnant women who receive high-dose gentamicin.
Several shortcomings of this study deserve mention. More than 85% of the subjects in our study were of white race and Hispanic ethnicity. Our data might be reliably extrapolated to other racial or ethnic populations; however, further study in other groups is needed before our conclusions can be generalized with a high degree of confidence. Although neonatal gentamicin toxicity is very unlikely to have occurred given the short duration of exposure, our methods of follow-up for these outcomes were not optimal. The most common manifestation of aminoglycoside nephrotoxicity is a mild elevation of the serum creatinine level. Severe acute tubular necrosis is a rare complication of prolonged gentamicin exposure.2 Measurement of urine output is performed routinely for neonates in our nursery. Measurements of neonatal urine output and serum creatinine levels were a part of our safety monitoring for this study; however, mild renal impairment could have occurred after the infants were discharged from the hospital. Hearing loss can occur several weeks after aminoglycoside therapy has been discontinued.2 Although we performed newborn hearing screening on all of our neonatal subjects before discharge from the hospital, these results do not eliminate the possibility of some auditory compromise.
The outcomes of gentamicin concentrations are surrogates for the much more important measures of maternal and neonatal morbidity. Although we did assess clinical outcomes and found no difference between groups, this study was not powered nearly enough to overcome type II error. Moreover, no infection-related morbidity was noted in our mothers or neonates. This probably relates to the clinical methods by which we diagnose chorioamnionitis. A larger presence of serious intra-amniotic infection among our study subjects could have affected clinical outcomes, the transfer of gentamicin across the placenta, or gentamicin clearance in the mothers or neonates. Further study, in larger populations, using once-daily dosing is needed to determine whether achieving higher peak values in mothers and fetuses translates to better perinatal outcomes. Further study will also provide more precise data on maternal, fetal, and amniotic fluid gentamicin elimination, particularly during the period from 5–12 hours after administration.
1. Duff P, Gibbs RS. Progress in the pathogenesis and management of clinical intraamniotic infection. Am J Obstet Gynecol 1991;164:1317–26.
2. Chambers HF. Antimicrobial agents: the aminoglycosides. In: Hardman JG, Limbird LE, Goodman Gilman A, editors. Goodman & Gilman's the pharmacological basis of therapeutics. New York (NY): The McGraw Hill Medical Publishing Division; 2001. p. 1219–38.
3. Gilbert DW. Once-daily aminoglycoside therapy. Antimicrob Agents Chemother 1991;35:399–405.
4. Noone P, Pattison JR, Davies DG. The effective use of gentamicin in life-threatening sepsis. Postgrad Med J 1974;50:9–16.
5. Moore RD, Lietman PS, Smith CR. Clinical response to aminoglycoside therapy: importance of the ratio of peak concentration to minimal inhibitory concentration. J Infect Dis 1987;155:93–9.
6. Del Priori G, Jackson-Stone M, Shim EK, Garfinkel J, Eichmann MA, Frederiksen MC. A comparison of once-daily and 8-hour gentamicin dosing in the treatment of postpartum endometritis. Obstet Gynecol 1996;87:994–1000.
7. Sunyecz JA, Wiesenfeld HC, Heine RP. The pharmacokinetics of once-daily dosing with gentamicin on women with postpartum endometritis. Infect Dis Obstet Gynecol 1998;6:160–2
8. Thureen PJ, Reiter PD, Gresores A, Stolpman NM, Kawato K, Hall DM. Once- versus twice-daily gentamicin dosing in neonates ≥ 34 weeks’ gestation: cost effectiveness analyses. Pediatrics 1999;103:594–8.
9. Mitra AG, Whitten K, Laurent SL, Anderson WE. A randomized, prospective study comparing once-daily gentamicin versus thrice-daily gentamicin in the treatment of puerperal infection. Am J Obstet Gynecol 1997;177:786–92.
11. Daïkos GL, Lolans VT, Jackson GG. First-exposure adaptive resistance to aminoglycoside antibiotics in vivo with meaning for optimal clinical use. Antimicrob Agents Chemother 1991;35:117–23.
12. Moore RD, Smith CR, Lietman PS. The association of aminoglycoside plasma levels with mortality in patients with gram-negative bacteremia. J Infect Dis 1984;149:443–8.
13. Lundergan FS, Glasscock GF, Kim EH, Cohen RS. Once-daily gentamicin in newborn infants. Pediatrics 1999;103:1228–34.
14. Lewis DB, Wilson CB. Developmental immunology and the role of host defenses in neonatal susceptibility to infection. In: Remington JS, Klein JO, editors. Infectious diseases of the fetus and newborn infant. Philadelphia (PA): WB Saunders; 1995. p. 20–98.
15. Wilson CB. Immunologic basis for increased susceptibility of the neonate to infection. J Pediatr 1986;108:1–12.
16. Weinstein A, Gibbs R, Gallagher M. Placental transfer of clindamycin and gentamicin in term pregnancy. Am J Obstet Gynecol 1976;124:688–91.
17. Watterberg KL, Kelly HW, Angelus P, Backstrom CL. The need for a loading dose of gentamicin in neonates. Ther Drug Monit 1989;11:16–20.
18. Semehuk W, Borgmann J, Bowman L. Determination of a gentamicin loading dose in neonates and infants. Ther Drug Monit 1993;15:47–51.
19. Isemann BT, Kotagal UR, Mashni SM, Luckhaupt EJ, Johnson CJ. Optimal gentamicin therapy in preterm neonates including loading doses and early monitoring. Ther Drug Mon 1996;18:549–55.
20. Regev RH, Litmanowitz I, Arnon S, Shiff J, Dolfin T. Gentamicin serum concentrations in neonates born to gentamicin-treated mothers. Pediatr Inf Dis J 2000;19:890–1.
21. Yow MD. An overview of pediatric experience with amikacin. Am J Med 1977;62:954–8.
22. Aronoff GR, Pottratz ST, Brier ME, Walker NE, Fineberg NS, Glant MD, et al. Aminoglycoside accumulation kinetics in the rat renal parenchyma. Antimicrob Agents Chemother 1983;23:74–8.
23. Lietman PS, Smith CR. Aminoglycoside nephrotoxicity in humans. J Infect Dis 1983;5(suppl):S284–92.
24. Patel V, Luft FC, Yum MN, Patel B, Zeman W, Kleit SA. Enzymuria in gentamicin-induced kidney damage. Antimicrob Agents Chemother 1975;7:364–9.
25. Schentag JJ, Gengo FM, Plaut ME, Danner D, Mangione A, Jusko WJ. Urinary casts as an indicator of renal tubular damage in patients receiving aminoglycosides. Antimicrob Agents Chemother 1979;16:468–74.
26. Theopold HM. Comparative surface studies of ototoxic effects of various aminoglycoside antibiotics on the organ of Corti in the guinea pig. A scanning electron microscopic study. Acta Otolaryngol 1977;84:57–64.
27. Wersäll J, Bjorkroth B, Flock A, Lundquist PG. Experiments in the ototoxic effects of antibiotics. Adv Otorhinolaryngol 1973;20:14–41.
28. Tran Ba Huy P, Bernard P, Schact J. Kinetics of gentamicin uptake and release in the rat: comparison of inner ear tissues and fluids with other organs. J Clin Invest 1986;77:1492–500.
29. McCormack JP, Jewesson PJ. A critical reevaluation of the “therapeutic range” of aminoglycosides. Clin Infect Dis 1992;14:320–9.
30. Laurent G, Kishore B, Tulkens P. Aminoglycoside-induced renal phospholipidosis and nephrotoxicity. Biochem Pharmacol 1990;40:2383–92.
31. Liu C, Abate B, Reyes M, Gonik B. Single daily dosing of gentamicin: pharmacokinetic comparison of two dosing methodologies for postpartum endometritis. Infect Dis Obstet Gynecol 1999;7:133–7.
32. Briggs GC, Ambrose P, Nageotte MP. Gentamicin dosing in postpartum women with endometritis. Am J Obstet Gynecol 1989;160:309–13.
33. Gardner DK, Schneider PJ. Gentamicin dosage requirements in postpartum patients. Clin Pharm 1984;3:416–8.
34. Munar MY, Lawson LA, Samuels P, Gibson GA. Gentamicin pharmacokinetics in postpartum women with endomyometritis. DICP 1991;25:1306–9.
35. Zaske DE, Cipolle RJ, Strate RG, Malo JW, Koszalska MF. Rapid gentamicin elimination in obstetric patients. Obstet Gynecol 1980;56:559–64.
36. Craig WA. Post-antibiotic effects on experimental infection models: relationship to in-vitro phenomena and to treatment of infections in man. J Antimicrob Chemother 1993;31:149–58.
37. Craig WA, Redington J, Ebert SC. Pharmacodynamics of amikacin in vitro and in mouse thigh and lung infections. J Antimicrob Chemother 1991;27:29–40.
38. Kapusnik JE, Hackbarth CJ, Chambers HF, Carpenter T, Sande MA. Single, large, daily dosing versus intermittent dosing of tobramycin for treating experimental pseudomonas pneumonia. J Infect Dis 1988;158:7–12.
39. Gudmundsson S, Einarsson S, Erlendsdottir H, Moffat J, Bayer W, Craig WA. The post-antibiotic effect of antimicrobial combinations in a neutropenic murine thigh infection model. J Antimicrob Chemother 1993;31:177–91.