Currently, there is no evidence whether ganciclovir, or its oral prodrug valganciclovir, penetrates into the cerebrospinal fluid of human infants treated for congenital cytomegalovirus infection. Here we report a case study providing evidence that ganciclovir, administered as valganciclovir, reaches the infant's cerebrospinal fluid when used at the currently recommended dose for congenital cytomegalovirus infection

Bizzarri, Bianca

Cardi, Veronica

DE CURTIS, Mario

Fabio, Natale

Gaeta, Aurelia

Giuseppina, Liuzzi

Paola, Villani

The Italian Journal of Pediatrics

English

PubMed

Fabio Natale

BIZZARRI, BIANCA

CARDI, VERONICA

GAETA, Aurelia

Paola Villani

Giuseppina Liuzzi

DE CURTIS, MARIO

Archivio della ricerca- Università di Roma La Sapienza

ITALIAN JOURNALOF PEDIATRICSNatale et al. Italian Journal of Pediatrics  (2015) 41:26 DOI 10.1186/s13052-015-0132-8CASE REPORT Open AccessGanciclovir penetrates into the cerebrospinal fluidof an infant with congenital cytomegalovirusinfectionFabio Natale1,5*, Bianca Bizzarri1, Veronica Cardi1, Aurelia Gaeta2, Paola Villani3, Giuseppina Liuzzi4and Mario De Curtis1AbstractCurrently, there is no evidence whether ganciclovir, or its oral prodrug valganciclovir, penetrates into thecerebrospinal fluid of human infants treated for congenital cytomegalovirus infection. Here, we report a case studyproviding evidence that ganciclovir, administered as valganciclovir, reaches the infant’s cerebrospinal fluid whenused at the currently recommended dose for congenital cytomegalovirus infection.Keywords: Valganciclovir, Ganciclovir, Cytomegalovirus, Cerebrospinal fluid, Congenital infectionBackgroundGanciclovir (GCV) is the drug of choice for the treatmentof congenital cytomegalovirus (CMV) infection. In fact,6 weeks intravenous GCV therapy, compared with no treat-ment, has been demonstrated to significantly prevent hear-ing deterioration [1] and developmental delays [2] ininfants with congenital CMV infection involving the centralnervous system. Valganciclovir (V-GCV), an oral pro-drugof GCV, nowadays represents a valuable alternative to GCVand, compared to GCV, does not require prolongedhospitalization and catheterization, thus avoiding consider-able costs for the Health Care System, and infectious risksfor the infants [3]. For both these drugs, cerebrospinal fluid(CSF) penetration has never been demonstrated in congeni-tally CMV infected infants undergoing antiviral therapy atthe currently recommended dosages.Case reportA 30-year-old woman had a primary CMV infection inthe first trimester of pregnancy (gestation week 9), de-fined by the presence of immunoglobulin (Ig) M andlow avidity IgG. At gestation week 20, CMV DNA was* Correspondence: fab.natale@libero.it1Department of Pediatrics and Child Neuropsychiatry, “La Sapienza”University of Rome, Rome, Italy5Neonatal Intensive Care Unit, Department of Pediatrics and ChildNeuropsychiatry, “Sapienza” University of Rome, V.le Regina Elena 324, 00161Rome, ItalyFull list of author information is available at the end of the article© 2015 Natale et al.; licensee BioMed Central.Commons Attribution License (http://creativecreproduction in any medium, provided the orDedication waiver (http://creativecommons.orunless otherwise stated.evidenced in the amniotic fluid sample at concentrationsof 3.8 × 105 genomic copies (GC)/mL. Intrauterinegrowth retardation was detected starting gestation week30. A foetal brain magnetic resonance imaging (MRI),performed two weeks later, was normal. A small for ges-tational age (<10° centile for gestational age) femaleinfant in good clinical conditions was delivered at38 weeks gestational age. Congenital CMV infection wasconfirmed by means of quantitative Polymerase ChainReaction (qPCR) performed on urine sampled on day oflife (dol) 2.On dol 11, the infant was referred to our centre toundergo a diagnostic workup for congenital CMV infection.Clinical examination, fundus oculi, abdominal and cerebralultrasound, and auditory brainstem evoked responses wereall negative; complete blood count and transaminase levelswere in the normal range for the infant’s age. Of note, abrain MRI performed at 1.5 Tesla (Magnetom Avanto, Sie-mens Medical Solution, Malvern, PA, USA) failed to findany brain lesions. CMV DNA search was performed onurine and blood samples by an automated system for nu-cleic acid extraction (Nuclisens EasyMag, Biomerieux) anda commercially available TaqMan Real Time PolymeraseChain Reaction kit (ELITech Group S.p.A.) for quantitativeCMV DNA amplification. According to our screening pro-cedure, and following informed consent by the parents, alumbar puncture for cerebrospinal fluid (CSF) CMV DNAThis is an Open Access article distributed under the terms of the Creativeommons.org/licenses/by/4.0), which permits unrestricted use, distribution, andiginal work is properly credited. The Creative Commons Public Domaing/publicdomain/zero/1.0/) applies to the data made available in this article,Natale et al. Italian Journal of Pediatrics  (2015) 41:26 Page 2 of 3search and CSF indices was carried out. CMV DNA wasdetected in all the samples tested (Table 1).Since the CMV-DNA search in the CSF was positive,on dol 20 we decided to start antiviral treatment with acommercial oral solution of V-GCV (Valcyte®, Roche S.p.A., Segrate, Italy) at 16 mg/kg/dose twice a day. Ondol 21, after the uneventful administration of two dosesof V-GCV, the baby was discharged home. The drugdosage was adjusted weekly according to the weight in-crease. During V-GCV therapy, complete blood count,transaminase, and creatinine levels were monitored threetimes (on dol 27, 45, and 55 respectively) for possibledrug toxicity: the first two blood tests were within thenormal range for the patient’s age whereas, on dol 55, aremarkable transaminase increase was detected (Alanineaminotransferase: 328 U/L, Aspartate Aminotransferase:400 U/L). Due to the onset of liver toxicity presumablyrelated to antiviral therapy, V-GCV was withdrawn ondol 55 (after 35 days of therapy) and never resumed. Fif-teen days later, transaminase levels were in the normalrange.CMV DNA qPCR on plasma, urine and CSF sampleswere again performed on dol 45 (Table 1). At the sametime, plasma trough and peak values (one hour before andtwo hours after V-GCV administration, respectively) andCSF GCV concentration (performed concomitantly withGCV plasma trough sample) were evaluated by means ofHigh-Performance Liquid Chromatography assay withfluorescence detection (Table 1). Ongoing clinical, oph-thalmological, audiological and neurological follow-up (bymeans of the Bayley Scales of Infant Development-III) isnormal at twelve months of age.Table 1 Summary of the laboratory findings obtained oncerebrospinal fluid, blood, and urine samples before (dol11) and after 25 days of Valganciclovir therapy (dol 45)Findings Dol 11 Dol 45Cerebrospinal FluidProteins 67,9 mg/dL 59,0 mg/dLWhite Cells 12 cells/μL 9 cells/μLRed Cells 141 cells/μL 373 cells/μLCMV-DNA 2.835.371 GC/ml NegativeGCV - 0,52 μg/mlBloodCMV-DNA 115.068 GC/ml 821 GC/mlGCV (trough) - 0,53 μg/mlGCV (peak) - 5,54 μg/mlUrineCMV-DNA >25.000.000 GC/ml 619.137 GC/mlSee text for the abbreviations.DiscussionA randomized, controlled trial, demonstrated that gan-ciclovir, administered at 6 mg/kg/dose twice a day for6 weeks intravenously, is able to prevent hearing deteri-oration [1] and developmental delays [2] in infants withcongenital CMV infection involving the central nervoussystem. V-GCV, an oral pro-drug of ganciclovir that israpidly converted into ganciclovir after intestinal ab-sorption, reached plasma concentrations comparable tothose achieved with administration of intravenous gan-ciclovir when used at 16 mg/kg/dose twice a day [4]. V-GCV has demonstrated to be well tolerated and is in-creasingly used because, compared to GCV, it does notrequire hospitalization and catheterization, thus avoid-ing considerable costs for the Health Care System andinfectious risks for the infants. Moreover, V-GCV seemsto be suitable for prolonged home therapy [3].The evaluation of CSF levels is used to predict braininterstitial fluid concentrations of a drug [5]. AlthoughGCV penetration into the CSF has been demonstratedin some reports dealing with CMV infected adults andchildren in different clinical situation (an adult sufferingrenal failure [6], a child with acute lymphoblastic leukemiawho exhibited a reduced creatinine clearance [7], and twobone marrow transplanted patients on different ganciclo-vir regimen therapy [8]), our report provides evidence, forthe first time, that GCV, administered as V-GCV, reachesthe infant’s CSF when used at the currently recommendeddosages for congenital CMV infection [4]. Our GCVplasma trough and peak concentrations (Table 1), detectedby means of a validated technique [9], were consistentwith those reported in the medical literature [3]; GCVplasma (trough value) and CSF levels (trough value) wereoverlapping in this case (Table 1), although additional re-sults are needed to establish any significant pharmacoki-netic correlation between plasma and CSF GCVconcentrations in neonates.CMV DNA qPCR performed on CSF before and duringV-GCV therapy (Table 1) showed a reduced viral load inthe CSF, suggestive of effective therapy on brain infection.Although the CSF GCV concentration of 0,52 μg/ml we re-ported was below the inhibitory concentration (IC) 50 formost CMV clinical isolates [10], it must be taken into ac-count that the CSF sample was drawn concomitantly withthe plasma trough sample, thus allowing a GCV CSF peaklevel over the requested IC 50. Besides, the CSF CMVDNA negativisation cannot be fully explained since the per-sistence of CMV DNA into the CSF of untreated infants isunknown.According to published guidelines [11], and in orderto prevent possible ongoing brain damage resulting fromCMV replication in the infant’s brain, we decided (fol-lowing the parents’ informed consent) to start V-GCVtherapy in this patient given the positive CSF CMVNatale et al. Italian Journal of Pediatrics  (2015) 41:26 Page 3 of 3DNA and despite normal CSF indices (Table 1) and neuro-imaging. Nonetheless, in our opinion, further studies arenecessary to evaluate the need for therapy, if any, in infantswith positive CSF CMV DNA and undetectable braindamage.ConsentWritten informed consent was obtained from the patient’sparents to publish this Case report. A copy of the writtenconsent can be submitted to the Editor-in-Chief of thisjournal.AbbreviationsGCV: Ganciclovir; CMV: Cytomegalovirus; V-GCV: Valganciclovir;CSF: Cerebrospinal fluid; Ig: Immunoglobulin; GC: Genomic copies;MRI: Magnetic Resonance Imaging; qPCR: quantitative Polymerase ChainReaction; DOL: Day of life; IC: inhibitory concentration.Competing interestsThe authors declare that they have no competing interests.Authors’ contributionsFN and BB conceived the study, reviewed the literature, and drafted themanuscript; VC collected the data and critically revised the manuscript; AGand GL performed the CMV DNA research on the biological samples of themother and infant; PV performed the drug dosages on plasma and CSFsamples; MdC made substantial contributions to conception and design ofthis report and critically revised the manuscript. All authors read andapproved the final manuscript.Author details1Department of Pediatrics and Child Neuropsychiatry, “La Sapienza”University of Rome, Rome, Italy. 2Laboratory of Virology, Department ofPublic Health and Infectious Diseases, “La Sapienza” University of Rome,Rome, Italy. 3Department of Pharmacology, IRCCS Policlinico S. Matteo, Pavia,Italy. 4I.N.M.I. Lazzaro Spallanzani, Rome, Italy. 5Neonatal Intensive Care Unit,Department of Pediatrics and Child Neuropsychiatry, “Sapienza” University ofRome, V.le Regina Elena 324, 00161 Rome, Italy.Received: 2 February 2015 Accepted: 22 March 2015References1. Kimberlin DW, Lin CY, Sánchez PJ, Demmler GJ, Dankner W, Shelton M,et al. Effect of ganciclovir therapy on hearing in symptomatic congenitalcytomegalovirus disease involving the central nervous system: arandomized, controlled trial. J Pediatr. 2003;143:16–25.2. Oliver SE, Cloud GA, Sánchez PJ, Demmler GJ, Dankner W, Shelton M, et al.Neurodevelopmental outcomes following ganciclovir therapy insymptomatic congenital cytomegalovirus infections involving the centralnervous system. J Clin Virol. 2009;46 Suppl 4:S22–6.3. Stronati M, Lombardi G, Garofoli F, Villani P, Regazzi M. Pharmacokinetics,pharmacodynamics and clinical use of valganciclovir in newborns withsymptomatic congenital cytomegalovirus infection. Curr Drug Metab.2013;14:208–15.4. Kimberlin DW, Acosta EP, Sánchez PJ, Sood S, Agrawal V, Homans J, et al.Pharmacokinetic and pharmacodynamic assessment of oral valganciclovir inthe treatment of symptomatic congenital cytomegalovirus disease. J InfectDis. 2008;197:836–45.5. Nau R, Sörgel F, Eiffert H. Penetration of drugs through the blood-cerebrospinal fluid/blood–brain barrier for treatment of central nervoussystem infections. Clin Microbiol Rev. 2010;23:858–83.6. Sakamoto H, Hirano M, Nose K, Ueno S, Oki T, Sugimoto K, et al. A case ofsevere ganciclovir-induced encephalopathy. Case Rep Neurol. 2013;5:183–6.7. Peyriere H, Jeziorsky E, Jalabert A, Cociglio M, Benketira A, Blayac JP, et al.Neurotoxicity related to valganciclovir in a child with impaired renalfunction: usefulness of therapeutic drug monitoring. Ann Pharmacother.2006;40:143–6.8. Fletcher C, Sawchuk R, Chinnock B, de Miranda P, Balfour Jr HH. Humanpharmacokinetics of the antiviral drug DHPG. Clin Pharmacol Ther.1986;40:281–6.9. Chu F, Kiang CH, Sung ML, Huang B, Reeve RL, Tarnowski T. A rapid,sensitive HPLC method for the determination of ganciclovir in humanplasma and serum. J Pharm Biomed Anal. 1999;21:657–67.10. McSharry JJ, McDonough A, Olson B, Talarico C, Davis M, Biron KK. Inhibitionof ganciclovir-susceptible and -resistant human cytomegalovirus clinicalisolates by the benzimidazole L-riboside 1263W94. Clin Diagn Lab Immunol.2001;8(6):1279–81.11. Kadambari S, Williams EJ, Luck S, Griffiths PD, Sharland M. Evidence basedmanagement guidelines for the detection and treatment of congenitalCMV. Early Hum Dev. 2011;87:723–8.Submit your next manuscript to BioMed Centraland take full advantage of: • Convenient online submission• Thorough peer review• No space constraints or color figure charges• Immediate publication on acceptance• Inclusion in PubMed, CAS, Scopus and Google Scholar• Research which is freely available for redistributionSubmit your manuscript at www.biomedcentral.com/submit

Ganciclovir penetrates into the cerebrospinal fluid of an infant with congenital cytomegalovirus infection

Bianca Bizzarri

Veronica Cardi

Aurelia Gaeta

Mario De Curtis

Crossref

ITALIAN JOURNALOF PEDIATRICSNatale et al. Italian Journal of Pediatrics  (2015) 41:26 DOI 10.1186/s13052-015-0132-8CASE REPORT Open AccessGanciclovir penetrates into the cerebrospinal fluidof an infant with congenital cytomegalovirusinfectionFabio Natale1,5*, Bianca Bizzarri1, Veronica Cardi1, Aurelia Gaeta2, Paola Villani3, Giuseppina Liuzzi4and Mario De Curtis1AbstractCurrently, there is no evidence whether ganciclovir, or its oral prodrug valganciclovir, penetrates into thecerebrospinal fluid of human infants treated for congenital cytomegalovirus infection. Here, we report a case studyproviding evidence that ganciclovir, administered as valganciclovir, reaches the infant’s cerebrospinal fluid whenused at the currently recommended dose for congenital cytomegalovirus infection.Keywords: Valganciclovir, Ganciclovir, Cytomegalovirus, Cerebrospinal fluid, Congenital infectionBackgroundGanciclovir (GCV) is the drug of choice for the treatmentof congenital cytomegalovirus (CMV) infection. In fact,6 weeks intravenous GCV therapy, compared with no treat-ment, has been demonstrated to significantly prevent hear-ing deterioration [1] and developmental delays [2] ininfants with congenital CMV infection involving the centralnervous system. Valganciclovir (V-GCV), an oral pro-drugof GCV, nowadays represents a valuable alternative to GCVand, compared to GCV, does not require prolongedhospitalization and catheterization, thus avoiding consider-able costs for the Health Care System, and infectious risksfor the infants [3]. For both these drugs, cerebrospinal fluid(CSF) penetration has never been demonstrated in congeni-tally CMV infected infants undergoing antiviral therapy atthe currently recommended dosages.Case reportA 30-year-old woman had a primary CMV infection inthe first trimester of pregnancy (gestation week 9), de-fined by the presence of immunoglobulin (Ig) M andlow avidity IgG. At gestation week 20, CMV DNA was* Correspondence: fab.natale@libero.it1Department of Pediatrics and Child Neuropsychiatry, “La Sapienza”University of Rome, Rome, Italy5Neonatal Intensive Care Unit, Department of Pediatrics and ChildNeuropsychiatry, “Sapienza” University of Rome, V.le Regina Elena 324, 00161Rome, ItalyFull list of author information is available at the end of the article© 2015 Natale et al.; licensee BioMed Central.Commons Attribution License (http://creativecreproduction in any medium, provided the orDedication waiver (http://creativecommons.orunless otherwise stated.evidenced in the amniotic fluid sample at concentrationsof 3.8 × 105 genomic copies (GC)/mL. Intrauterinegrowth retardation was detected starting gestation week30. A foetal brain magnetic resonance imaging (MRI),performed two weeks later, was normal. A small for ges-tational age (<10° centile for gestational age) femaleinfant in good clinical conditions was delivered at38 weeks gestational age. Congenital CMV infection wasconfirmed by means of quantitative Polymerase ChainReaction (qPCR) performed on urine sampled on day oflife (dol) 2.On dol 11, the infant was referred to our centre toundergo a diagnostic workup for congenital CMV infection.Clinical examination, fundus oculi, abdominal and cerebralultrasound, and auditory brainstem evoked responses wereall negative; complete blood count and transaminase levelswere in the normal range for the infant’s age. Of note, abrain MRI performed at 1.5 Tesla (Magnetom Avanto, Sie-mens Medical Solution, Malvern, PA, USA) failed to findany brain lesions. CMV DNA search was performed onurine and blood samples by an automated system for nu-cleic acid extraction (Nuclisens EasyMag, Biomerieux) anda commercially available TaqMan Real Time PolymeraseChain Reaction kit (ELITech Group S.p.A.) for quantitativeCMV DNA amplification. According to our screening pro-cedure, and following informed consent by the parents, alumbar puncture for cerebrospinal fluid (CSF) CMV DNAThis is an Open Access article distributed under the terms of the Creativeommons.org/licenses/by/4.0), which permits unrestricted use, distribution, andiginal work is properly credited. The Creative Commons Public Domaing/publicdomain/zero/1.0/) applies to the data made available in this article,Natale et al. Italian Journal of Pediatrics  (2015) 41:26 Page 2 of 3search and CSF indices was carried out. CMV DNA wasdetected in all the samples tested (Table 1).Since the CMV-DNA search in the CSF was positive,on dol 20 we decided to start antiviral treatment with acommercial oral solution of V-GCV (Valcyte®, Roche S.p.A., Segrate, Italy) at 16 mg/kg/dose twice a day. Ondol 21, after the uneventful administration of two dosesof V-GCV, the baby was discharged home. The drugdosage was adjusted weekly according to the weight in-crease. During V-GCV therapy, complete blood count,transaminase, and creatinine levels were monitored threetimes (on dol 27, 45, and 55 respectively) for possibledrug toxicity: the first two blood tests were within thenormal range for the patient’s age whereas, on dol 55, aremarkable transaminase increase was detected (Alanineaminotransferase: 328 U/L, Aspartate Aminotransferase:400 U/L). Due to the onset of liver toxicity presumablyrelated to antiviral therapy, V-GCV was withdrawn ondol 55 (after 35 days of therapy) and never resumed. Fif-teen days later, transaminase levels were in the normalrange.CMV DNA qPCR on plasma, urine and CSF sampleswere again performed on dol 45 (Table 1). At the sametime, plasma trough and peak values (one hour before andtwo hours after V-GCV administration, respectively) andCSF GCV concentration (performed concomitantly withGCV plasma trough sample) were evaluated by means ofHigh-Performance Liquid Chromatography assay withfluorescence detection (Table 1). Ongoing clinical, oph-thalmological, audiological and neurological follow-up (bymeans of the Bayley Scales of Infant Development-III) isnormal at twelve months of age.Table 1 Summary of the laboratory findings obtained oncerebrospinal fluid, blood, and urine samples before (dol11) and after 25 days of Valganciclovir therapy (dol 45)Findings Dol 11 Dol 45Cerebrospinal FluidProteins 67,9 mg/dL 59,0 mg/dLWhite Cells 12 cells/μL 9 cells/μLRed Cells 141 cells/μL 373 cells/μLCMV-DNA 2.835.371 GC/ml NegativeGCV - 0,52 μg/mlBloodCMV-DNA 115.068 GC/ml 821 GC/mlGCV (trough) - 0,53 μg/mlGCV (peak) - 5,54 μg/mlUrineCMV-DNA >25.000.000 GC/ml 619.137 GC/mlSee text for the abbreviations.DiscussionA randomized, controlled trial, demonstrated that gan-ciclovir, administered at 6 mg/kg/dose twice a day for6 weeks intravenously, is able to prevent hearing deteri-oration [1] and developmental delays [2] in infants withcongenital CMV infection involving the central nervoussystem. V-GCV, an oral pro-drug of ganciclovir that israpidly converted into ganciclovir after intestinal ab-sorption, reached plasma concentrations comparable tothose achieved with administration of intravenous gan-ciclovir when used at 16 mg/kg/dose twice a day [4]. V-GCV has demonstrated to be well tolerated and is in-creasingly used because, compared to GCV, it does notrequire hospitalization and catheterization, thus avoid-ing considerable costs for the Health Care System andinfectious risks for the infants. Moreover, V-GCV seemsto be suitable for prolonged home therapy [3].The evaluation of CSF levels is used to predict braininterstitial fluid concentrations of a drug [5]. AlthoughGCV penetration into the CSF has been demonstratedin some reports dealing with CMV infected adults andchildren in different clinical situation (an adult sufferingrenal failure [6], a child with acute lymphoblastic leukemiawho exhibited a reduced creatinine clearance [7], and twobone marrow transplanted patients on different ganciclo-vir regimen therapy [8]), our report provides evidence, forthe first time, that GCV, administered as V-GCV, reachesthe infant’s CSF when used at the currently recommendeddosages for congenital CMV infection [4]. Our GCVplasma trough and peak concentrations (Table 1), detectedby means of a validated technique [9], were consistentwith those reported in the medical literature [3]; GCVplasma (trough value) and CSF levels (trough value) wereoverlapping in this case (Table 1), although additional re-sults are needed to establish any significant pharmacoki-netic correlation between plasma and CSF GCVconcentrations in neonates.CMV DNA qPCR performed on CSF before and duringV-GCV therapy (Table 1) showed a reduced viral load inthe CSF, suggestive of effective therapy on brain infection.Although the CSF GCV concentration of 0,52 μg/ml we re-ported was below the inhibitory concentration (IC) 50 formost CMV clinical isolates [10], it must be taken into ac-count that the CSF sample was drawn concomitantly withthe plasma trough sample, thus allowing a GCV CSF peaklevel over the requested IC 50. Besides, the CSF CMVDNA negativisation cannot be fully explained since the per-sistence of CMV DNA into the CSF of untreated infants isunknown.According to published guidelines [11], and in orderto prevent possible ongoing brain damage resulting fromCMV replication in the infant’s brain, we decided (fol-lowing the parents’ informed consent) to start V-GCVtherapy in this patient given the positive CSF CMVNatale et al. Italian Journal of Pediatrics  (2015) 41:26 Page 3 of 3DNA and despite normal CSF indices (Table 1) and neuro-imaging. Nonetheless, in our opinion, further studies arenecessary to evaluate the need for therapy, if any, in infantswith positive CSF CMV DNA and undetectable braindamage.ConsentWritten informed consent was obtained from the patient’sparents to publish this Case report. A copy of the writtenconsent can be submitted to the Editor-in-Chief of thisjournal.AbbreviationsGCV: Ganciclovir; CMV: Cytomegalovirus; V-GCV: Valganciclovir;CSF: Cerebrospinal fluid; Ig: Immunoglobulin; GC: Genomic copies;MRI: Magnetic Resonance Imaging; qPCR: quantitative Polymerase ChainReaction; DOL: Day of life; IC: inhibitory concentration.Competing interestsThe authors declare that they have no competing interests.Authors’ contributionsFN and BB conceived the study, reviewed the literature, and drafted themanuscript; VC collected the data and critically revised the manuscript; AGand GL performed the CMV DNA research on the biological samples of themother and infant; PV performed the drug dosages on plasma and CSFsamples; MdC made substantial contributions to conception and design ofthis report and critically revised the manuscript. All authors read andapproved the final manuscript.Author details1Department of Pediatrics and Child Neuropsychiatry, “La Sapienza”University of Rome, Rome, Italy. 2Laboratory of Virology, Department ofPublic Health and Infectious Diseases, “La Sapienza” University of Rome,Rome, Italy. 3Department of Pharmacology, IRCCS Policlinico S. Matteo, Pavia,Italy. 4I.N.M.I. Lazzaro Spallanzani, Rome, Italy. 5Neonatal Intensive Care Unit,Department of Pediatrics and Child Neuropsychiatry, “Sapienza” University ofRome, V.le Regina Elena 324, 00161 Rome, Italy.Received: 2 February 2015 Accepted: 22 March 2015References1. Kimberlin DW, Lin CY, Sánchez PJ, Demmler GJ, Dankner W, Shelton M,et al. Effect of ganciclovir therapy on hearing in symptomatic congenitalcytomegalovirus disease involving the central nervous system: arandomized, controlled trial. J Pediatr. 2003;143:16–25.2. Oliver SE, Cloud GA, Sánchez PJ, Demmler GJ, Dankner W, Shelton M, et al.Neurodevelopmental outcomes following ganciclovir therapy insymptomatic congenital cytomegalovirus infections involving the centralnervous system. J Clin Virol. 2009;46 Suppl 4:S22–6.3. Stronati M, Lombardi G, Garofoli F, Villani P, Regazzi M. Pharmacokinetics,pharmacodynamics and clinical use of valganciclovir in newborns withsymptomatic congenital cytomegalovirus infection. Curr Drug Metab.2013;14:208–15.4. Kimberlin DW, Acosta EP, Sánchez PJ, Sood S, Agrawal V, Homans J, et al.Pharmacokinetic and pharmacodynamic assessment of oral valganciclovir inthe treatment of symptomatic congenital cytomegalovirus disease. J InfectDis. 2008;197:836–45.5. Nau R, Sörgel F, Eiffert H. Penetration of drugs through the blood-cerebrospinal fluid/blood–brain barrier for treatment of central nervoussystem infections. Clin Microbiol Rev. 2010;23:858–83.6. Sakamoto H, Hirano M, Nose K, Ueno S, Oki T, Sugimoto K, et al. A case ofsevere ganciclovir-induced encephalopathy. Case Rep Neurol. 2013;5:183–6.7. Peyriere H, Jeziorsky E, Jalabert A, Cociglio M, Benketira A, Blayac JP, et al.Neurotoxicity related to valganciclovir in a child with impaired renalfunction: usefulness of therapeutic drug monitoring. Ann Pharmacother.2006;40:143–6.8. Fletcher C, Sawchuk R, Chinnock B, de Miranda P, Balfour Jr HH. Humanpharmacokinetics of the antiviral drug DHPG. Clin Pharmacol Ther.1986;40:281–6.9. Chu F, Kiang CH, Sung ML, Huang B, Reeve RL, Tarnowski T. A rapid,sensitive HPLC method for the determination of ganciclovir in humanplasma and serum. J Pharm Biomed Anal. 1999;21:657–67.10. McSharry JJ, McDonough A, Olson B, Talarico C, Davis M, Biron KK. Inhibitionof ganciclovir-susceptible and -resistant human cytomegalovirus clinicalisolates by the benzimidazole L-riboside 1263W94. Clin Diagn Lab Immunol.2001;8(6):1279–81.11. Kadambari S, Williams EJ, Luck S, Griffiths PD, Sharland M. Evidence basedmanagement guidelines for the detection and treatment of congenitalCMV. Early Hum Dev. 2011;87:723–8.Submit your next manuscript to BioMed Centraland take full advantage of: • Convenient online submission• Thorough peer review• No space constraints or color ﬁgure charges• Immediate publication on acceptance• Inclusion in PubMed, CAS, Scopus and Google Scholar• Research which is freely available for redistributionSubmit your manuscript at www.biomedcentral.com/submit

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Ganciclovir penetrates into the cerebrospinal fluid of an infant with congenital cytomegalovirus infection

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