R Jacobs

University of Arkansas at Little Rock, Little Rock, Arkansas, United States

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Publications (12)156.25 Total impact

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    ABSTRACT: The treatment of symptomatic congenital cytomegalovirus (CMV) disease with intravenous ganciclovir for 6 weeks has been shown to improve audiologic outcomes at 6 months, but the benefits wane over time. We conducted a randomized, placebo-controlled trial of valganciclovir therapy in neonates with symptomatic congenital CMV disease, comparing 6 months of therapy with 6 weeks of therapy. The primary end point was the change in hearing in the better ear ("best-ear" hearing) from baseline to 6 months. Secondary end points included the change in hearing from baseline to follow-up at 12 and 24 months and neurodevelopmental outcomes, with each end point adjusted for central nervous system involvement at baseline. A total of 96 neonates underwent randomization, of whom 86 had follow-up data at 6 months that could be evaluated. Best-ear hearing at 6 months was similar in the 6-month group and the 6-week group (2 and 3 participants, respectively, had improvement; 36 and 37 had no change; and 5 and 3 had worsening; P=0.41). Total-ear hearing (hearing in one or both ears that could be evaluated) was more likely to be improved or to remain normal at 12 months in the 6-month group than in the 6-week group (73% vs. 57%, P=0.01). The benefit in total-ear hearing was maintained at 24 months (77% vs. 64%, P=0.04). At 24 months, the 6-month group, as compared with the 6-week group, had better neurodevelopmental scores on the Bayley Scales of Infant and Toddler Development, third edition, on the language-composite component (P=0.004) and on the receptive-communication scale (P=0.003). Grade 3 or 4 neutropenia occurred in 19% of the participants during the first 6 weeks. During the next 4.5 months of the study, grade 3 or 4 neutropenia occurred in 21% of the participants in the 6-month group and in 27% of those in the 6-week group (P=0.64). Treating symptomatic congenital CMV disease with valganciclovir for 6 months, as compared with 6 weeks, did not improve hearing in the short term but appeared to improve hearing and developmental outcomes modestly in the longer term. (Funded by the National Institute of Allergy and Infectious Diseases; ClinicalTrials.gov number, NCT00466817.).
    New England Journal of Medicine 03/2015; 372(10):933-43. DOI:10.1056/NEJMoa1404599 · 54.42 Impact Factor
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    ABSTRACT: Background: Neonatal enterovirus (EV) infections have high morbidity & mortality. Antiviral therapy is not currently available. Pleconaril is an oral capsid binder with activity against EVs. Methods: Neonates with suspected EV sepsis (hepatitis, coagulopathy, or myocarditis) were randomized 2:1 to receive oral pleconaril or placebo x 7 days. Specimens (oropharynx, rectum, urine, serum) for viral culture & polymerase chain reaction (PCR), pharmacokinetic analysis, & safety evaluations were obtained over 14 days & clinical assessments were performed over 24 months. Results: 61 subjects were enrolled (43 treatment, 18 placebo), of whom 43 were confirmed EV-infected by culture or PCR (31 treatment, 12 placebo). Baseline characteristics were similar between EV-infected groups; median (range) age at illness onset was 4.5 (1-15) & 5.0 (1-10) days, respectively. Low culture yields precluded demonstrating a difference in the primary endpoint, day 5 oropharyngeal culture positivity (25% positive on Day 1 & 0% on Day 5 in the treatment group v. 30% on Day 1 & 0% on Day 5 in the placebo group). However, subjects in the treatment group became culture-negative from all anatomic sites combined faster than subjects in the placebo group (Fig 1; median 4.0 v. 7.0 days, p = 0.08) & fewer subjects in the treatment group remained PCR-positive from the oropharynx when last sampled (83% positive on Day 1 & 23% positive at a median of 14 days in the treatment group v. 100% positive on Day 1 & 58% positive at a median of 14 days in the placebo group, p = 0.02). By intent to treat, 10/43 (23%) of all subjects in the treatment group & 8/18 (44%) in the placebo group died (Fig 2; p = 0.02 for 2 month survival difference). Among EV-confirmed subjects, 7/31 (23%) in the treatment group died v. 5/12 (42%) in the placebo group (Fig 3; p = 0.26). Pleconaril concentrations exceeded the IC90 after the first treatment day, but 41% of subjects did not achieve this targetduring the 1st treatment day. 1 subject in the treatment group & 3 in the placebo group had treatment-related adverse events. Conclusion: Shorter times to culture & PCR negativity & suggestion of greater survival among pleconaril recipients support potential efficacy & warrant further evaluation. SEQ Figure * ARABIC 1. Culture positive SEQ Figure * ARABIC 2. Survival, all subjects SEQ Figure * ARABIC 3. Survival, EV-confirmed
    IDWeek 2014 Meeting of the Infectious Diseases Society of America; 10/2014
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    ABSTRACT: The study sought to determine the relationship between cytomegalovirus (CMV) viremia during early infancy and clinical and laboratory outcome events, particularly hearing loss in infants with symptomatic congenital CMV infection involving the central nervous system (CNS). A total of 147 infant patients were enrolled prospectively in 2 clinical trials evaluating ganciclovir for the treatment of symptomatic congenital CMV infection involving the CNS. Aliquots of serum collected at enrollment in either of the 2 trials were available from 50 of the infants, and the degree of viremia was determined by real-time quantitative polymerase chain reaction. Of the 50 infants from whom serum samples were available, 37 had detectable CMV DNA in the serum sample collected at enrollment and were classified as viremic. Viremic infants were more likely to have (1) hearing loss both at enrollment (P = .045) and at the 6-month follow-up testing (P = .035) and (2) other indicators of active CMV disease, including elevated levels of alanine aminotransferase, petechial rash, and organomegaly. In children with symptomatic congenital CMV infection involving the CNS, viremia during early infancy is associated with hearing loss and systemic CMV disease.
    The Journal of Infectious Diseases 02/2005; 191(2):227-33. DOI:10.1086/426456 · 5.78 Impact Factor
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    The Journal of Infectious Diseases 12/1996; 174(6). DOI:10.1093/infdis/174.6.1162 · 5.78 Impact Factor
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    ABSTRACT: The population pharmacokinetics of ganciclovir was investigated in a group of 27 newborns with symptomatic congenital cytomegalovirus infection by nonlinear mixed-effects modeling analysis. Individual characteristics including approximated creatinine clearance from serum (ASCC) and body weight (WGE) were identified to significantly influence total clearance from plasma (CL) and the apparent total volume of distribution (V) of ganciclovir, respectively. The regression equations used to model these relationships were expressed as CL (in liters per hour) = 0.262 + (0.00271 x ASCC) and V (in liters) = 0.627 + (0.437 x WGE). By using this model, typical values of the pharmacokinetic parameter CL and V were 0.428 +/- 0.079 liters/h and 1.773 +/- 0.320 liters, respectively. Upon validation with a larger number of newborns, this model should allow for the definition of possible relationships between the pharmacokinetic disposition of ganciclovir and pharmacodynamic events in neonates.
    Antimicrobial Agents and Chemotherapy 10/1996; 40(9):2202-5. · 4.45 Impact Factor
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    ABSTRACT: Neonatal herpes simplex virus (HSV) infections limited to the skin, eyes and mouth (SEM) can result in neurologic impairment. A direct correlation exists between the development of neurologic deficits and the frequency of cutaneous HSV recurrences. Thus, the National Institutes of Allergy and Infectious Diseases Collaborative Antiviral Study Group conducted a Phase I/II trial of oral acyclovir therapy for the suppression of cutaneous recurrences after SEM disease in 26 neonates. Infants < or = 1 month of age with virologically confirmed HSV-2 SEM disease were eligible for enrollment. Suppressive oral acyclovir therapy (300 mg/m2/dose given either twice daily or three times per day) was administered for 6 months. Twelve (46%) of the 26 infants developed neutropenia (< 1000 cells/mm3) while receiving acyclovir. Thirteen (81%) of the 16 infants who received drug 3 times per day experienced no recurrences of skin lesions while receiving therapy. In comparison, a previous Collaborative Antiviral Study Group study found that only 54% of infants have no cutaneous recurrences in the 6 months after resolution of neonatal HSV disease if oral acyclovir suppressive therapy is not initiated. In one infant, HSV DNA was detected in the cerebrospinal fluid during a cutaneous recurrence, and an acyclovir-resistant HSV mutant was isolated from another patient during the course of the study. Administration of oral acyclovir can prevent cutaneous recurrences of HSV after neonatal SEM disease. The effect of such therapy on neurologic outcome must be assessed in a larger, Phase III study. As such, additional investigation is necessary before routine use of suppressive therapy in this population can be recommended.
    The Pediatric Infectious Disease Journal 04/1996; 15(3):247-54. DOI:10.1097/00006454-199603000-00014 · 3.14 Impact Factor
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    ABSTRACT: The population pharmacokinetics of ganciclovir was investigated in a group of 27 newborns with symptomatic congenital cytomegalovirus infection by nonlinear mixed-effects modeling analysis. Individual characteristics including approximated creatinine clearance from serum (ASCC) and body weight (WGE) were identified to significantly influence total clearance from plasma (CL) and the apparent total volume of distribution (V) of ganciclovir, respectively. The regression equations used to model these relationships were expressed as CL (in liters per hour) = 0.262 + (0.00271 x ASCC) and V (in liters) = 0.627 + (0.437 x WGE). By using this model, typical values of the pharmacokinetic parameter CL and V were 0.428 ± 0.079 liters/h and 1.773 ± 0.320 liters, respectively. Upon validation with a larger number of newborns, this model should allow for the definition of possible relationships between the pharmacokinetic disposition of ganciclovir and pharmacodynamic events in neonates.
    Clinical Pharmacology &#38 Therapeutics 02/1996; 59(2):184-184. DOI:10.1038/sj.clpt.1996.236 · 7.39 Impact Factor
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    ABSTRACT: The pharmacokinetic characteristics of ganciclovir were determined in neonates (age range, 2 to 49 days) after an 1-hour intravenous infusion of a single dose of either 4 mg/kg (n = 14) or 6 mg/kg (n = 13). Twenty-seven newborns with symptomatic cytomegalovirus inclusion disease were enrolled in this open phase I-II pharmacokinetics, safety, and tolerance trial of ganciclovir at one of two doses. Ganciclovir disposition was best described by a one-compartment open model with zero-order input and first-order elimination. The mean elimination half-life (t((1/2))) for both dose groups was 2.4 hours. The mean apparent volume of distribution (Vd) was 669 +/- 70 ml/kg for the 4 mg/kg group and 749 +/- 59 ml/kg for the 6 mg/kg group. The mean total body clearance (CL) for the 4 mg/kg and 6 mg/kg groups was 189 +/- 28 ml/hr/kg and 213 +/- 21 ml/hr/kg, respectively. No significant differences were observed in Vd or CL between the two groups. The Vd, expressed in milliliters, increased with increasing patient weight (r = 0.689; p = 0.0001). The CL, expressed in milliliters per hour per kilogram, increased with increasing age (r = 0.413; p = 0.032). No significant differences were observed between the two dose groups for the area under the curve normalized for dose (AUC/Dose) or the maximum plasma concentration normalized for dose (C(max)/Dose), indicating that ganciclovir exhibited linear pharmacokinetics in these neonates.Clinical Pharmacology and Therapeutics (1993) 53, 15-21; doi:10.1038/clpt.1993.4.
    Clinical Pharmacology &#38 Therapeutics 02/1993; 53(1):15-21. DOI:10.1038/clpt.1993.4 · 7.39 Impact Factor
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    ABSTRACT: The pharmacokinetic characteristics of ganciclovir were determined in neonates (age range, 2 to 49 days) after an 1-hour intravenous infusion of a single dose of either 4 mg/kg (n = 14) or 6 mg/kg (n = 13). Twenty-seven newborns with symptomatic cytomegalovirus inclusion disease were enrolled in this open phase I-II pharmacokinetics, safety, and tolerance trial of ganciclovir at one of two doses. Ganciclovir disposition was best described by a one-compartment open model with zero-order input and first-order elimination. The mean elimination half-life (t1/2) for both dose groups was 2.4 hours. The mean apparent volume of distribution (Vd) was 669 +/- 70 ml/kg for the 4 mg/kg group and 749 +/- 59 ml/kg for the 6 mg/kg group. The mean total body clearance (CL) for the 4 mg/kg and 6 mg/kg groups was 189 +/- 28 ml/hr/kg and 213 +/- 21 ml/hr/kg, respectively. No significant differences were observed in Vd or CL between the two groups. The Vd, expressed in milliliters, increased with increasing patient weight (r = 0.689; p = 0.0001). The CL, expressed in milliliters per hour per kilogram, increased with increasing age (r = 0.413; p = 0.032). No significant differences were observed between the two dose groups for the area under the curve normalized for dose (AUC/Dose) or the maximum plasma concentration normalized for dose (Cmax/Dose), indicating that ganciclovir exhibited linear pharmacokinetics in these neonates.
    Clinical Pharmacology &#38 Therapeutics 02/1993; 53(1):15-21. · 7.39 Impact Factor
  • Obstetrical and Gynecological Survey 01/1992; 37(1):68-69. DOI:10.1016/0020-7292(92)90998-X · 2.36 Impact Factor
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    ABSTRACT: In a controlled trial comparing acyclovir with vidarabine in the treatment of neonatal herpes simplex virus (HSV) infection, we found no significant difference between the treatments in adjusted mortality and morbidity. Hence, we sought to define for the entire cohort (n = 202) the clinical characteristics that best predicted the eventual outcome in these neonates. Data were gathered prospectively at 27 centers between 1981 and 1988 in infants less than one month of age who had virologically confirmed HSV infection. We examined the outcomes by multivariate analyses of 24 variables. Disease was classified in one of three categories based on the extent of the involvement at entry into the trial: infection confined to skin, eyes, or mouth; encephalitis; or disseminated infection. There were no deaths among the 85 infants with localized HSV infection. The mortality rate was significantly higher in the 46 neonates with disseminated infection (57 percent) than in the 71 with encephalitis (15 percent). In addition, the risk of death was increased in neonates who were in or near coma at entry (relative risk, 5.2), had disseminated intravascular coagulopathy (relative risk, 3.8), or were premature (relative risk, 3.7). In babies with disseminated disease, HSV pneumonitis was also associated with greater mortality (relative risk, 3.6). In the survivors, morbidity was most frequent in infants with encephalitis (relative risk, 4.4), disseminated infection (relative risk, 2.1), seizures (relative risk, 3.0), or infection with HSV type 2 (relative risk, 4.9). With HSV infection limited to the skin, eyes, or mouth, the presence of three or more recurrences of vesicles was associated with an increased risk of neurologic impairment as compared with two or fewer recurrences.
    New England Journal of Medicine 03/1991; 324(7):450-4. DOI:10.1056/NEJM199102143240704 · 54.42 Impact Factor
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    ABSTRACT: Neonatal herpes simplex virus (HSV) infection is usually acquired at birth, although a few infants have had findings suggestive of intrauterine infection. We describe 13 babies who had clinical manifestations of intrauterine HSV infection, including skin lesions and scars at birth (12), chorioretinitis (eight), microcephaly (seven), hydranencephaly (five), and microphthalmia (two). All infants had combinations of these defects. Infection was proved by viral isolation in each case; all isolates were HSV-2. Two infants died during the first week of life; 10 of the surviving infants had severe neurologic sequelae, and one infant was blind. Four mothers experienced an apparent primary genital HSV infection, and one had recurrent infection, at varying times during gestation. The remaining women denied a history of symptoms of genital HSV infection. These findings indicate that intrauterine HSV infection can occur as a consequence of either primary or recurrent maternal infection and has severe consequences for the fetus.
    Journal of Pediatrics 02/1987; 110(1):97-101. DOI:10.1016/S0022-3476(87)80298-6 · 3.74 Impact Factor