Obstetrics & Gynecology:
High Compared With Standard Gentamicin Dosing for Chorioamnionitis: A Comparison of Maternal and Fetal Serum Drug Levels
Locksmith, Gregory J. MD*; Chin, Anita MD*; Vu, Tammy MD*; Shattuck, Karen E. MD†; Hankins, Gary D. V. MD*
From the *Department of Obstetrics & Gynecology, Division of Maternal-Fetal Medicine, and †Department of Pediatrics, Division of Neonatology, University of Texas Medical Branch, Galveston, Texas.
Presented at the Annual Meeting of the Society for Maternal-Fetal Medicine, February 3–7, 2004, New Orleans, Louisiana.
Reprints are not available. Address correspondence to: Gregory J. Locksmith, MD, Arnold Palmer Hospital for Children and Women, 105 West Miller Street, Orlando, Florida 32806; e-mail: email@example.com.
Received July 30, 2004. Received in revised form October 1, 2004. Accepted October 14, 2004.
OBJECTIVE: To compare umbilical cord and maternal serum peak gentamicin concentration, gentamicin elimination, and clinical outcomes between women who received once-daily compared with standard, thrice-daily dosing for clinical chorioamnionitis.
METHODS: We randomly assigned 38 laboring women, at least 34 weeks gestation, with clinical chorioamnionitis, into 1 of 2 gentamicin dosing groups: 5.1 mg/kg every 24 hours (once-daily; n = 18), or 120 mg followed by 80 mg every 8 hours (standard; n = 20). We measured maternal serum peak and delivery gentamicin concentrations and cord serum levels at delivery. Polynomial curve fitting was used to summarize gentamicin elimination. We also compared maternal and neonatal outcomes.
RESULTS: Demographic characteristics of the 2 groups were similar. Median maternal peak gentamicin levels were higher with once-daily (18.2 μg/mL) compared with standard dosing (7.1 μg/mL) (P < .001). Maternal serum levels decreased below 2 μg/mL by 10 hours in the once-daily group and by 5 hours in the standard dosing group. Extrapolated peak cord serum levels were 6.9 μg/mL in the once-daily and 2.9 μg/mL in the standard dosing arm. Cord levels decreased below 2 μg/mL by 10 hours in the once-daily and by 5 hours in the standard dosing group. We found no differences in maternal or neonatal outcomes.
CONCLUSION: Peak maternal serum gentamicin levels ranged from 13 to 25 μg/mL after a dose of 5.1 mg/kg. Single-dose gentamicin resulted in fetal serum peak levels that were closer to optimal neonatal values. Gentamicin clearance in the term fetus was similar to published values for the newborn infant. No adverse effects of high-dose therapy were noted.
LEVEL OF EVIDENCE: II-3
The standard of care for acute chorioamnionitis is antibiotic therapy immediately upon making the diagnosis. The primary rationale behind this practice is to reduce the risk of neonatal sepsis.1 Although universal agreement does not exist regarding the antibiotic regimen of choice, most studies to date have evaluated intravenous ampicillin (2 g every 6 hours) plus gentamicin (1.0–1.5 mg/kg every 8 hours).1 Concerns about using gentamicin and other aminoglycosides in pregnancy are rooted in their potential to cause kidney or eighth cranial nerve damage in the mother or neonate.2 Administering the total daily dose of gentamicin once daily, rather than in divided doses, has been proposed as a means of reducing toxicity.3 Higher doses of aminoglycoside antibiotics administered at longer intervals also result in higher peak levels and longer duration of bacterial killing after serum drug concentrations fall below the minimum inhibitory concentration (MIC), purportedly improving efficacy.4,5 One could also argue, however, that shorter dosing intervals are preferable with a bacteriocidal agent such as gentamicin. Improved effectiveness and reduced toxicity have been difficult to demonstrate in prospective studies, but once-daily dosing has been shown to be more cost-effective than traditional dosing.6–9
We undertook this investigation in laboring women with clinical chorioamnionitis primarily to compare fetal and maternal peak serum gentamicin concentrations between subjects who received once-daily compared with standard, thrice-daily dosing of gentamicin. We also compared gentamicin elimination between the two study groups. Maternal and neonatal clinical outcomes were evaluated secondarily.
MATERIALS AND METHODS
This randomized study was approved by the University of Texas Medical Branch Institutional Review Board. From November 25, 2001, through May 5, 2003, we enrolled 38 women of at least 34 weeks gestation with clinical chorioamnionitis. The diagnosis of chorioamnionitis was based on a fever during labor of at least 37.8°C combined with at least 1 of the following clinical signs: maternal heart rate greater than 100 beats per minute, fetal heart rate greater than 160 beats per minute, uterine tenderness, or malodorous amniotic fluid. In the interest of patient safety, we excluded women with a history of renal insufficiency or myasthenia gravis, serum creatinine level greater than 1.4 mg/dL, allergy to gentamicin, receipt of magnesium sulfate or a neuromuscular blocking agent within 24 hours of enrollment, hypocalcemia, or receipt of a diuretic agent within the week before enrollment. To reduce confounding, women with coexisting maternal infection requiring systemic antibiotic therapy also were excluded.
After providing informed consent, subjects were randomly assigned to 1 of 2 gentamicin dosing groups: conventional dosing (n = 20), and once-daily dosing (n = 18). Randomization was accomplished with sequentially numbered sealed, opaque envelopes. A randomization schedule was created by using a computer-generated random number table. Women assigned to the conventional dosing group received a 120 mg loading dose followed by 80 mg every 8 hours. Women assigned to the once-daily dosing group received 5.1 mg/kg of ideal or adjusted body weight every 24 hours. Ideal body weight (in kilograms) was calculated by adding 2.3 kg for every inch in the subject's height over five feet to a base of 45.5 kg. If the subject's actual body weight was more than 30% greater than her ideal body weight, an adjusted weight was used to derive her dose of gentamicin by adding her ideal body weight to 40% of the difference between her actual and ideal body weight. Ampicillin 2 g intravenously every 6 hours, was also provided to all subjects.
Maternal serum gentamicin levels were obtained 30 minutes after completion of each dose (peak) and at delivery. We also measured umbilical cord serum gentamicin concentrations at delivery. From these values we constructed elimination curves for each dosing group, in both maternal and fetal compartments, plotting gentamicin concentration against time. For the mothers, we calculated an elimination constant (ke) in each subject using the following formula: ke = ln(C1/C2)/(t1−t2),10 where C1 is the peak gentamicin concentration, C2 is the concentration at delivery, and t1-t2 is the interval from drug administration to delivery. With the elimination constant, the half-life (t1/2) for each subject was calculated using the following formula: t1/2 = 0.693/ke.10 Because only 1 umbilical cord serum sample was taken from each fetal subject, elimination constants and half-lives were calculated for each study group by selecting 2 points on each composite elimination curve that encompassed the highest concentration of data points.
We compared the following maternal outcomes between the 2 groups: duration of labor after a diagnosis of chorioamnionitis, cesarean delivery rate, length of febrile illness in the postpartum period, and length of hospitalization. Evaluations of specific maternal morbidity included puerperal infection, peripartum hemorrhage, need for blood transfusion, and death. Neonatal outcomes of interest included Apgar scores, urine output (assessed by daily diaper counts), serum creatinine levels, suspected and confirmed sepsis rates, need for antibiotic therapy, length of antibiotic therapy, length of hospitalization, and death. Practitioners who performed the initial neonatal physical examination were instructed to note specifically the presence or absence of respiratory depression and neuromuscular weakness. Additionally, neonates underwent audiologic evaluation as part of a state mandated hearing screening program for newborn infants before discharge. Those with abnormal tests were referred to the audiology service for follow-up diagnostic testing.
Reviewers who assessed outcomes were blinded to the assignment of patients to treatment groups. Categorically defined outcomes were compared using χ2 and Fisher exact tests where appropriate. Outcomes defined on a continuous scale with normal distribution were compared with the Student t test. Ordinal variables and continuous variables that were not normally distributed were compared using the Mann-Whitney U test. Pearson correlation was used to evaluate the relationship between umbilical cord serum gentamicin concentrations and time from their mothers’ last dose. A significance level of 0.05 and a power level of 0.80 were selected. To detect a 1.5 μg/mL difference in peak fetal gentamicin levels, assuming a range of values between 4 and 10 μg/mL, a sample size of 17 subjects per group was required.
Overall, 45 women were invited to participate in the study. Thirty-eight subjects provided consent. Eighteen subjects were randomly assigned to once-daily dosing, and 17 of these provided maternal peak serum samples, 17 provided serum samples at delivery, and cord serum samples were obtained in 17. Of the 20 subjects assigned to the standard dosing group, 17 provided maternal peak serum samples, 18 provided serum samples at delivery, and cord samples were obtained in 19. All of the subjects in the once-daily group received only 1 dose of gentamicin before delivery. Dosages in the once-daily dosing group ranged from 280–410 mg. All subjects in the standard dosing group received 120 mg of gentamicin with their first dose. One subject in the conventional dosing group received 2 gentamicin doses before delivery, and the remainder received only 1 dose. Maternal characteristics at the time of enrollment are depicted in Table 1. The isolated maternal gentamicin concentration obtained right after the second dose of 80 mg was not used for determination of the median peak value in Table 2. Clinical outcomes were analyzed in all 38 subject pairs. Dosing groups did not differ significantly with respect to demographic characteristics, gestational age, fetal weight, and clinical criteria for chorioamnionitis. All subjects were in labor at the time of enrollment.
Figure 1 displays maternal serum peak gentamicin concentrations and levels at delivery in the once-daily and conventional dosing groups. Mean maternal peak levels were 18.1 μg/mL in the once-daily and 7.5 μg/mL in the conventional dosing group (P < .001). Maternal serum levels decreased to below 2 μg/mL by 10 hours in the once-daily group and by 5 hours in the standard dosing group.
Umbilical cord serum gentamicin levels at the time of delivery are depicted in Figure 2. Strong inverse correlations between fetal gentamicin concentration and time from the mother's last dose were noted with both once-daily (r = −0.79, P < .001) and conventional dosing (r = −0.76, P < .001). Three subjects from each group delivered within 1 hour of receiving their first dose. Mean cord serum levels from these women were 6.5 μg/mL (once-daily) and 3.0 μg/mL (standard) (P = .04). A best fit elimination curve was constructed, and the extrapolated peak cord serum levels were similar to these mean values (once-daily 6.9 μg/mL, standard 2.9 μg/mL). From this curve, fetal serum half-lives were estimated at 5.6 hours in the once-daily dosing group and at 4.5 hours in the standard dosing group. Cord serum levels decreased to below 2 μg/mL by 10 hours in the once-daily group and by 5 hours in the standard dosing group.
Maternal outcomes are presented in Table 2. After the clinical diagnosis of chorioamnionitis was made, there were no differences in duration of labor, cesarean rate, duration of maternal fever, overall maternal morbidity, or duration of hospital stay. No maternal deaths occurred. Table 3 lists neonatal outcomes. At the time of birth, neither Apgar scores nor signs of neuromuscular weakness differed between groups. No cases of culture-positive sepsis, respiratory depression, or inadequate urine production were found, and no perinatal deaths occurred. Rates of suspected sepsis requiring antibiotic use were similar, as was the duration of neonatal antibiotic administration between groups. No difference in mean serum creatinine levels was found between the 2 groups, and none of the neonates in this study demonstrated evidence of compromised urinary output. Overall morbidity and length of hospitalization among the neonatal groups were similar. One infant, from the standard maternal dosing group, had an abnormal hearing screening examination that was found on follow-up diagnostic evaluation to be normal.
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.
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