Antimicrobial Reports
Achievement of Therapeutic Vancomycin Trough Serum Concentrations with Empiric Dosing in Neonatal Intensive Care Unit Patients Theresa Ringenberg, PharmD, BCPS,* Christine Robinson, PharmD,*† Rachel Meyers, PharmD, BCPS,*‡ Lisa Degnan, PharmD, BCPS,*§ Pooja Shah, PharmD,*§ Anita Siu, PharmD,*¶ and Marc Sturgill, PharmD*‖ Background: The recommended goal serum trough concentration for vancomycin has increased to 10 to 20 mcg/mL, with a higher range of 15 to 20 mcg/mL for serious infections due to methicillin-resistant Staphylococcus aureus in children and adults. Although neonatal references have also recommended these higher target concentrations, dosing recommendations remained unchanged. The objective of this study was to assess the percentage of neonates and young infants achieving a serum trough concentration between 10 and 20 mcg/mL with empiric vancomycin dosing based on Neofax® in a neonatal intensive care unit (NICU) population. Methods: A multi-institutional retrospective chart review was conducted to identify NICU patients who received a minimum of three doses of intravenous vancomycin and had at least one appropriately drawn trough. Additional outcomes included the duration of vancomycin therapy, number of dose adjustments required to attain goal trough concentrations, time to goal trough, and incidence of nephrotoxicity and ototoxicity. Results: Of the 171 vancomycin serum trough concentrations included in the primary outcome, only 25.1% achieved a goal trough of 10 to 20 mcg/mL with empiric dosing. Only 44.6% of patients achieved the goal trough of 10 to 20 mcg/mL at any time during their vancomycin therapy. The average gestational age was 28.2 ± 4.1 weeks, average postnatal age at start of vancomycin was 34.1 ± 34.6 days, and average weight of the patients at start of vancomycin was 1602 ± 1014.5 g. The average and median total daily dose in those patients who achieved an initial vancomycin trough of 10–20 mcg/mL were 32.4 mg/kg/day and 30 mg/kg/day, respectively. Conclusion: Dosing of vancomycin based on Neofax® in NICU patients is insufficient in yielding serum trough concentrations of 10 to 20 mcg/mL. Further studies are needed to evaluate the optimal dosing regimen to achieve higher trough concentrations in this patient population. Key Words: vancomycin, neonates, trough (Pediatr Infect Dis J 2015;34:742–747)
V
ancomycin is commonly prescribed in the neonatal intensive care unit (NICU) for empiric treatment of late-onset sepsis.1 The most common causes of late-onset sepsis in NICU patients are coagulase negative staphylococcus (CoNS) and Staphylococcus aureus, occurring in 45 to 50% and 13% of patients, respectively.1–3 Due to the increasing resistance of staphylococcal strains, vancomycin is often Accepted for publication October 26, 2014. From the *Ernest Mario School of Pharmacy at Rutgers, The State University of New Jersey, Chicago, IL; †Morristown Medical Center, Morristown, NJ; ‡Saint Barnabas Medical Center, Livingston, NJ; §Hackensack University Medical Center, Hackensack, NJ; ¶Jersey Shore University Medical Center, Neptune City, NJ; and ‖Rutgers-Robert Wood Johnson Medical School, Piscataway, NJ. The authors declare no conflict of interest. Address for correspondence: Theresa Ringenberg, PharmD, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, 160 Frelinghuysen Road, Piscataway, NJ 08854. E-mail: christine.robinson@ atlantichealth.org. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. ISSN: 0891-3668/15/3407-0742 DOI: 10.1097/INF.0000000000000664
742 | www.pidj.com
used as empiric therapy.1,4 Vancomycin dosing in neonates ranges from 10 to 15 mg/kg/dose based on the indication, with the frequency based on postmenstrual (PMA) and postnatal (PNA) ages.5 Vancomycin is the drug of choice for treatment of invasive infections due to methicillin-resistant S. aureus (MRSA), including neonatal sepsis, according to the Infectious Disease Society of America (IDSA) 2011 MRSA guidelines.4 In 2006, the Antimicrobial Susceptibility Testing Subcommittee of the Clinical and Laboratory Standards Institute changed the susceptibility breakpoint in the minimum inhibitory concentration (MIC) for S. aureus isolates to vancomycin from less than or equal to 4 mcg/mL to less than or equal to 2 mcg/mL.4,6,7 A current concern with vancomycin revolves around the nationwide increase in the MIC of MRSA, or the “MIC creep.”8 A number of adult studies report an increase in clinical failure rates and mortality with vancomycin when used to treat MRSA isolates with vancomycin MICs that are at the higher end of the susceptibility range.9–13 Due to the concern with increasing vancomycin MICs in many institutions, higher total daily doses of vancomycin may be necessary.9,10 In 2009, the IDSA, American Society of Health Systems Pharmacists and the Society of Infectious Diseases consensus guidelines for vancomycin recommended that vancomycin troughs remain above 10 mcg/mL to aid in the avoidance of resistance. Also, trough concentrations of 15 to 20 mcg/mL were recommended in the 2011 IDSA MRSA guidelines to improve bacterial killing with vancomycin when used to treat serious MRSA infections in adults.4 Although Neofax® has updated their goal trough recommendation for vancomycin from 5 to 10 mcg/mL to 10 to 20 mcg/mL, a new dosing regimen to achieve the higher trough goal was not addressed.5 A literature review did not yield results for any studies evaluating the ability to achieve vancomycin serum trough concentrations of 10 to 20 mcg/mL in NICU patients with current dosing recommendations. The purpose of this study was to evaluate the feasibility of achieving a trough between 10 and 20 mcg/mL in NICU patients with initial vancomycin dosing as recommended by Neofax®.
MATERIALS AND METHODS Study Design A multi-institutional retrospective chart review was conducted to identify NICU patients who received intravenous vancomycin. The study received institutional review board approval at all sites. Four level III NICUs were included in the study. Patients in the NICU who received a minimum of three doses of intravenous vancomycin and had at least one appropriately drawn trough concentration between July 1, 2010 and June 30, 2012 were included. Vancomycin troughs were excluded if they were drawn inappropriately (ie, drawn more than 1 hour before the next scheduled vancomycin dose). To increase the likelihood of evaluating steady-state concentrations, troughs drawn before the second dose of vancomycin were also excluded. Steady-state was defined as 33 hours and 10 hours from the initial dose for infants with a PMA at the start of vancomycin therapy of
The Pediatric Infectious Disease Journal • Volume 34, Number 7, July 2015
Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
The Pediatric Infectious Disease Journal • Volume 34, Number 7, July 2015
Neonatal Vancomycin Trough Concentrations
less than 34 weeks and greater than or equal to 34 weeks, respectively. Finally, patients who had renal dysfunction before the initiation of vancomycin [ie, serum creatinine (SCr) greater than 1.5 mg/dL or urine output less 1 mL/kg/h over the preceding 24 hours] were also excluded.15,16 All institutions empirically dosed vancomycin in the NICU based on Neofax® recommendations.
Outcome Assessments The primary outcome was the percentage of NICU patients achieving a trough between 10 and 20 mcg/mL with initial vancomycin dosing as recommended by Neofax®. A trough of 10 to 20 mcg/mL may be necessary to eradicate serious staphylococal infections caused by MRSA.4 Trough concentrations were drawn by the hospital laboratory and not calculated using pharmacokinetics. Secondary outcomes included length of vancomycin therapy, number of dose adjustments required to achieve goal trough concentrations (10 to 20 mcg/mL), time to goal trough, incidence of nephrotoxicity and ototoxicity, and use of concomitant nephrotoxic medications. Nephrotoxicity was defined as a doubling of the SCr from baseline. Ototoxicity was defined as the infant failing his or her hearing screening performed near discharge. The overall achievement of any vancomycin serum trough concentration of 10 to 20 mcg/mL at any time during vancomycin therapy was also evaluated; one institution was excluded from this analysis because the institution’s goal vancomycin trough was 5 to 10 mcg/mL. To evaluate the aforementioned secondary outcome, the first vancomycin trough concentration within the range of 10 to 20 mcg/mL was used for data analysis.
Statistical Analysis Multivariate linear regression analysis was performed on all patients included in the primary outcome analysis to evaluate potential correlations between vancomycin serum trough concentrations and gestational age (GA), PNA, PMA, total daily dose of vancomycin, vancomycin dosing interval, birth weight, weight at the start of vancomycin therapy, aminoglycoside use and SCr at the initiation of vancomycin. A Mann–Whitney U test was performed to determine differences in the baseline characteristics between the patients who achieved a trough of at least 10 mcg/mL and those who did not.
Results
FIGURE 1. Primary outcome patient selection. common infection types were CoNS (33.3%) and S. aureus (18.5%; Fig. 3). Overall, 31.5% of all infection types were methicillin resistant (5.6% MRSA, 25.9% methicillin-resistant CoNS). Over half of the patients (58.6%) had negative blood cultures. The most common infection sources were blood (47.2%) and wound cultures (16.7%; Table 2). With initial vancomycin dosing, 71.9% of patients had a trough value of less than 10 mcg/mL, 25.1% achieved the trough goal of 10 to 20 mcg/mL, and 2.9% of patients had a trough over 20 mcg/mL (range 20.7–28.5 mcg/mL; Table 3). Of the 5 patients whose troughs were greater than 20 mcg/mL, the average GA was
N = 203 Patients with at least 1 appropriately drawn trough at any time during treatment
A total of 141 patient charts, representing 203 appropriately drawn vancomycin troughs (some patients were on vancomycin therapy more than once during their admission), were reviewed. However, 10 of these troughs were excluded because the initial trough was not drawn appropriately and they were from the institution that was excluded in the overall attainment of trough analysis. Therefore, 193 vancomycin troughs were evaluated between all primary and secondary outcomes. For the primary outcome, 15 vancomycin troughs were excluded because the initial trough was drawn inappropriately and 17 vancomycin troughs were excluded because the initial trough was not at steady-state (Fig. 1). Therefore, 171 vancomycin troughs were included in the primary outcome analysis and safety outcome analysis. For the secondary outcome of overall achievement of at least one serum trough concentrations of 10 to 20 mcg/mL, 3 vancomycin troughs were excluded because the troughs were drawn inappropriately, 32 troughs were excluded because the patients were from the institution whose trough goal is less than 10 mcg/mL, leaving 168 for inclusion (Fig. 2). Baseline characteristics are summarized in Table 1. The average GA was 28.2 weeks; 59.1% of patients were born at a GA of less than 28 weeks and 31.6% at a GA of 28 to 34 weeks. On average, patients started vancomycin at a PNA of 34.1 days and weight of 1602 g, and received vancomycin for 6.5 days. The most
FIGURE 2. Secondary outcome: achievement of at least one vancomycin trough of 10 to 20 mcg/mL patient inclusion.
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved
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N = 32 excluded Institution goal trough 20 mcg/mL 5 (2.9) Overall troughs (n = 168) 0–10 mcg/mL 92 (54.8) 10–20 mcg/mL 75 (44.6) > 20 mcg/mL 1 (0.6) # dose adjustments to attain trough 10–20 mcg/mL (n = 75) 0 48 (64) 1 22 (29.3) 2 5 (6.7) Duration of therapy to achieve 2.27 ± 1.76 days trough 10–20 mcg/mL (mean ±SD)
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved
Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
The Pediatric Infectious Disease Journal • Volume 34, Number 7, July 2015
TABLE 4. Concomitant Nephrotoxins Nephrotoxin
Number of Patients (%)
Acyclovir Aminoglycoside Amphotericin B Indomethacin % of patients on 1 % of patients on 2 % of patients on 3
2 (1) 86 (44.6) 10 (5.2) 11 (5.7) 91 (47.2) 8 (4.2) 1 (0.5)
TABLE 5. Multivariate Linear Regression Analysis of Covariates Associated with Vancomycin Trough Achievement Covariate
Gestational age Postnatal age Postmenstrual age Total daily dose Dosing interval Birth weight Weight at start of vancomycin Aminoglycoside use Serum creatinine
All Neonates (n = 171) P Value
PMA < 28 Wk (n = 36) P Value
PMA 28–34 Wk (n = 74) P Value
PMA > 34 Wk (n = 61) P Value
0.055 0.025 0.045
Achievement of Therapeutic Vancomycin Trough Serum Concentrations with Empiric Dosing in Neonatal Intensive Care Unit Patients Theresa Ringenberg, PharmD, BCPS,* Christine Robinson, PharmD,*† Rachel Meyers, PharmD, BCPS,*‡ Lisa Degnan, PharmD, BCPS,*§ Pooja Shah, PharmD,*§ Anita Siu, PharmD,*¶ and Marc Sturgill, PharmD*‖ Background: The recommended goal serum trough concentration for vancomycin has increased to 10 to 20 mcg/mL, with a higher range of 15 to 20 mcg/mL for serious infections due to methicillin-resistant Staphylococcus aureus in children and adults. Although neonatal references have also recommended these higher target concentrations, dosing recommendations remained unchanged. The objective of this study was to assess the percentage of neonates and young infants achieving a serum trough concentration between 10 and 20 mcg/mL with empiric vancomycin dosing based on Neofax® in a neonatal intensive care unit (NICU) population. Methods: A multi-institutional retrospective chart review was conducted to identify NICU patients who received a minimum of three doses of intravenous vancomycin and had at least one appropriately drawn trough. Additional outcomes included the duration of vancomycin therapy, number of dose adjustments required to attain goal trough concentrations, time to goal trough, and incidence of nephrotoxicity and ototoxicity. Results: Of the 171 vancomycin serum trough concentrations included in the primary outcome, only 25.1% achieved a goal trough of 10 to 20 mcg/mL with empiric dosing. Only 44.6% of patients achieved the goal trough of 10 to 20 mcg/mL at any time during their vancomycin therapy. The average gestational age was 28.2 ± 4.1 weeks, average postnatal age at start of vancomycin was 34.1 ± 34.6 days, and average weight of the patients at start of vancomycin was 1602 ± 1014.5 g. The average and median total daily dose in those patients who achieved an initial vancomycin trough of 10–20 mcg/mL were 32.4 mg/kg/day and 30 mg/kg/day, respectively. Conclusion: Dosing of vancomycin based on Neofax® in NICU patients is insufficient in yielding serum trough concentrations of 10 to 20 mcg/mL. Further studies are needed to evaluate the optimal dosing regimen to achieve higher trough concentrations in this patient population. Key Words: vancomycin, neonates, trough (Pediatr Infect Dis J 2015;34:742–747)
V
ancomycin is commonly prescribed in the neonatal intensive care unit (NICU) for empiric treatment of late-onset sepsis.1 The most common causes of late-onset sepsis in NICU patients are coagulase negative staphylococcus (CoNS) and Staphylococcus aureus, occurring in 45 to 50% and 13% of patients, respectively.1–3 Due to the increasing resistance of staphylococcal strains, vancomycin is often Accepted for publication October 26, 2014. From the *Ernest Mario School of Pharmacy at Rutgers, The State University of New Jersey, Chicago, IL; †Morristown Medical Center, Morristown, NJ; ‡Saint Barnabas Medical Center, Livingston, NJ; §Hackensack University Medical Center, Hackensack, NJ; ¶Jersey Shore University Medical Center, Neptune City, NJ; and ‖Rutgers-Robert Wood Johnson Medical School, Piscataway, NJ. The authors declare no conflict of interest. Address for correspondence: Theresa Ringenberg, PharmD, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, 160 Frelinghuysen Road, Piscataway, NJ 08854. E-mail: christine.robinson@ atlantichealth.org. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. ISSN: 0891-3668/15/3407-0742 DOI: 10.1097/INF.0000000000000664
742 | www.pidj.com
used as empiric therapy.1,4 Vancomycin dosing in neonates ranges from 10 to 15 mg/kg/dose based on the indication, with the frequency based on postmenstrual (PMA) and postnatal (PNA) ages.5 Vancomycin is the drug of choice for treatment of invasive infections due to methicillin-resistant S. aureus (MRSA), including neonatal sepsis, according to the Infectious Disease Society of America (IDSA) 2011 MRSA guidelines.4 In 2006, the Antimicrobial Susceptibility Testing Subcommittee of the Clinical and Laboratory Standards Institute changed the susceptibility breakpoint in the minimum inhibitory concentration (MIC) for S. aureus isolates to vancomycin from less than or equal to 4 mcg/mL to less than or equal to 2 mcg/mL.4,6,7 A current concern with vancomycin revolves around the nationwide increase in the MIC of MRSA, or the “MIC creep.”8 A number of adult studies report an increase in clinical failure rates and mortality with vancomycin when used to treat MRSA isolates with vancomycin MICs that are at the higher end of the susceptibility range.9–13 Due to the concern with increasing vancomycin MICs in many institutions, higher total daily doses of vancomycin may be necessary.9,10 In 2009, the IDSA, American Society of Health Systems Pharmacists and the Society of Infectious Diseases consensus guidelines for vancomycin recommended that vancomycin troughs remain above 10 mcg/mL to aid in the avoidance of resistance. Also, trough concentrations of 15 to 20 mcg/mL were recommended in the 2011 IDSA MRSA guidelines to improve bacterial killing with vancomycin when used to treat serious MRSA infections in adults.4 Although Neofax® has updated their goal trough recommendation for vancomycin from 5 to 10 mcg/mL to 10 to 20 mcg/mL, a new dosing regimen to achieve the higher trough goal was not addressed.5 A literature review did not yield results for any studies evaluating the ability to achieve vancomycin serum trough concentrations of 10 to 20 mcg/mL in NICU patients with current dosing recommendations. The purpose of this study was to evaluate the feasibility of achieving a trough between 10 and 20 mcg/mL in NICU patients with initial vancomycin dosing as recommended by Neofax®.
MATERIALS AND METHODS Study Design A multi-institutional retrospective chart review was conducted to identify NICU patients who received intravenous vancomycin. The study received institutional review board approval at all sites. Four level III NICUs were included in the study. Patients in the NICU who received a minimum of three doses of intravenous vancomycin and had at least one appropriately drawn trough concentration between July 1, 2010 and June 30, 2012 were included. Vancomycin troughs were excluded if they were drawn inappropriately (ie, drawn more than 1 hour before the next scheduled vancomycin dose). To increase the likelihood of evaluating steady-state concentrations, troughs drawn before the second dose of vancomycin were also excluded. Steady-state was defined as 33 hours and 10 hours from the initial dose for infants with a PMA at the start of vancomycin therapy of
The Pediatric Infectious Disease Journal • Volume 34, Number 7, July 2015
Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
The Pediatric Infectious Disease Journal • Volume 34, Number 7, July 2015
Neonatal Vancomycin Trough Concentrations
less than 34 weeks and greater than or equal to 34 weeks, respectively. Finally, patients who had renal dysfunction before the initiation of vancomycin [ie, serum creatinine (SCr) greater than 1.5 mg/dL or urine output less 1 mL/kg/h over the preceding 24 hours] were also excluded.15,16 All institutions empirically dosed vancomycin in the NICU based on Neofax® recommendations.
Outcome Assessments The primary outcome was the percentage of NICU patients achieving a trough between 10 and 20 mcg/mL with initial vancomycin dosing as recommended by Neofax®. A trough of 10 to 20 mcg/mL may be necessary to eradicate serious staphylococal infections caused by MRSA.4 Trough concentrations were drawn by the hospital laboratory and not calculated using pharmacokinetics. Secondary outcomes included length of vancomycin therapy, number of dose adjustments required to achieve goal trough concentrations (10 to 20 mcg/mL), time to goal trough, incidence of nephrotoxicity and ototoxicity, and use of concomitant nephrotoxic medications. Nephrotoxicity was defined as a doubling of the SCr from baseline. Ototoxicity was defined as the infant failing his or her hearing screening performed near discharge. The overall achievement of any vancomycin serum trough concentration of 10 to 20 mcg/mL at any time during vancomycin therapy was also evaluated; one institution was excluded from this analysis because the institution’s goal vancomycin trough was 5 to 10 mcg/mL. To evaluate the aforementioned secondary outcome, the first vancomycin trough concentration within the range of 10 to 20 mcg/mL was used for data analysis.
Statistical Analysis Multivariate linear regression analysis was performed on all patients included in the primary outcome analysis to evaluate potential correlations between vancomycin serum trough concentrations and gestational age (GA), PNA, PMA, total daily dose of vancomycin, vancomycin dosing interval, birth weight, weight at the start of vancomycin therapy, aminoglycoside use and SCr at the initiation of vancomycin. A Mann–Whitney U test was performed to determine differences in the baseline characteristics between the patients who achieved a trough of at least 10 mcg/mL and those who did not.
Results
FIGURE 1. Primary outcome patient selection. common infection types were CoNS (33.3%) and S. aureus (18.5%; Fig. 3). Overall, 31.5% of all infection types were methicillin resistant (5.6% MRSA, 25.9% methicillin-resistant CoNS). Over half of the patients (58.6%) had negative blood cultures. The most common infection sources were blood (47.2%) and wound cultures (16.7%; Table 2). With initial vancomycin dosing, 71.9% of patients had a trough value of less than 10 mcg/mL, 25.1% achieved the trough goal of 10 to 20 mcg/mL, and 2.9% of patients had a trough over 20 mcg/mL (range 20.7–28.5 mcg/mL; Table 3). Of the 5 patients whose troughs were greater than 20 mcg/mL, the average GA was
N = 203 Patients with at least 1 appropriately drawn trough at any time during treatment
A total of 141 patient charts, representing 203 appropriately drawn vancomycin troughs (some patients were on vancomycin therapy more than once during their admission), were reviewed. However, 10 of these troughs were excluded because the initial trough was not drawn appropriately and they were from the institution that was excluded in the overall attainment of trough analysis. Therefore, 193 vancomycin troughs were evaluated between all primary and secondary outcomes. For the primary outcome, 15 vancomycin troughs were excluded because the initial trough was drawn inappropriately and 17 vancomycin troughs were excluded because the initial trough was not at steady-state (Fig. 1). Therefore, 171 vancomycin troughs were included in the primary outcome analysis and safety outcome analysis. For the secondary outcome of overall achievement of at least one serum trough concentrations of 10 to 20 mcg/mL, 3 vancomycin troughs were excluded because the troughs were drawn inappropriately, 32 troughs were excluded because the patients were from the institution whose trough goal is less than 10 mcg/mL, leaving 168 for inclusion (Fig. 2). Baseline characteristics are summarized in Table 1. The average GA was 28.2 weeks; 59.1% of patients were born at a GA of less than 28 weeks and 31.6% at a GA of 28 to 34 weeks. On average, patients started vancomycin at a PNA of 34.1 days and weight of 1602 g, and received vancomycin for 6.5 days. The most
FIGURE 2. Secondary outcome: achievement of at least one vancomycin trough of 10 to 20 mcg/mL patient inclusion.
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved
www.pidj.com | 743
N = 32 excluded Institution goal trough 20 mcg/mL 5 (2.9) Overall troughs (n = 168) 0–10 mcg/mL 92 (54.8) 10–20 mcg/mL 75 (44.6) > 20 mcg/mL 1 (0.6) # dose adjustments to attain trough 10–20 mcg/mL (n = 75) 0 48 (64) 1 22 (29.3) 2 5 (6.7) Duration of therapy to achieve 2.27 ± 1.76 days trough 10–20 mcg/mL (mean ±SD)
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved
Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
The Pediatric Infectious Disease Journal • Volume 34, Number 7, July 2015
TABLE 4. Concomitant Nephrotoxins Nephrotoxin
Number of Patients (%)
Acyclovir Aminoglycoside Amphotericin B Indomethacin % of patients on 1 % of patients on 2 % of patients on 3
2 (1) 86 (44.6) 10 (5.2) 11 (5.7) 91 (47.2) 8 (4.2) 1 (0.5)
TABLE 5. Multivariate Linear Regression Analysis of Covariates Associated with Vancomycin Trough Achievement Covariate
Gestational age Postnatal age Postmenstrual age Total daily dose Dosing interval Birth weight Weight at start of vancomycin Aminoglycoside use Serum creatinine
All Neonates (n = 171) P Value
PMA < 28 Wk (n = 36) P Value
PMA 28–34 Wk (n = 74) P Value
PMA > 34 Wk (n = 61) P Value
0.055 0.025 0.045
