Cerebrospinal Pharmacokinetic Analysis and Pharmacodynamic Evaluation of Ceftriaxone in Pediatric Patients with Bacterial Meningitis
Corresponding Author
Tetsushu Onita
Department of Pharmacy, Shimane University Hospital, 89-1 Enya, Izumo, Shimane 693-8501, Japan shimane-u.ac.jp
Department of Clinical Pharmacotherapy, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan hiroshima-u.ac.jp
Search for more papers by this authorKazuro Ikawa
Department of Clinical Pharmacotherapy, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan hiroshima-u.ac.jp
Search for more papers by this authorNoriyuki Ishihara
Department of Pharmacy, Shimane University Hospital, 89-1 Enya, Izumo, Shimane 693-8501, Japan shimane-u.ac.jp
Search for more papers by this authorHiroki Tamaki
Department of Pharmacy, Shimane University Hospital, 89-1 Enya, Izumo, Shimane 693-8501, Japan shimane-u.ac.jp
Search for more papers by this authorTakahisa Yano
Department of Pharmacy, Shimane University Hospital, 89-1 Enya, Izumo, Shimane 693-8501, Japan shimane-u.ac.jp
Search for more papers by this authorNorifumi Morikawa
Department of Clinical Pharmacotherapy, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan hiroshima-u.ac.jp
Search for more papers by this authorKohji Naora
Department of Pharmacy, Shimane University Hospital, 89-1 Enya, Izumo, Shimane 693-8501, Japan shimane-u.ac.jp
Search for more papers by this authorCorresponding Author
Tetsushu Onita
Department of Pharmacy, Shimane University Hospital, 89-1 Enya, Izumo, Shimane 693-8501, Japan shimane-u.ac.jp
Department of Clinical Pharmacotherapy, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan hiroshima-u.ac.jp
Search for more papers by this authorKazuro Ikawa
Department of Clinical Pharmacotherapy, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan hiroshima-u.ac.jp
Search for more papers by this authorNoriyuki Ishihara
Department of Pharmacy, Shimane University Hospital, 89-1 Enya, Izumo, Shimane 693-8501, Japan shimane-u.ac.jp
Search for more papers by this authorHiroki Tamaki
Department of Pharmacy, Shimane University Hospital, 89-1 Enya, Izumo, Shimane 693-8501, Japan shimane-u.ac.jp
Search for more papers by this authorTakahisa Yano
Department of Pharmacy, Shimane University Hospital, 89-1 Enya, Izumo, Shimane 693-8501, Japan shimane-u.ac.jp
Search for more papers by this authorNorifumi Morikawa
Department of Clinical Pharmacotherapy, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan hiroshima-u.ac.jp
Search for more papers by this authorKohji Naora
Department of Pharmacy, Shimane University Hospital, 89-1 Enya, Izumo, Shimane 693-8501, Japan shimane-u.ac.jp
Search for more papers by this authorAbstract
What Is Known? and Objective. Ceftriaxone has been widely used to treat bacterial meningitis in pediatric patients. Ceftriaxone dosing regimens of 80–120 mg/kg/day have been recommended for bacterial meningitis in pediatric patients, and the usual duration of therapy is 7–14 days. Although the target site for meningitis is cerebrospinal fluid (CSF), a CSF pharmacokinetic (PK) model in pediatric patients has not been reported. We aimed to develop a CSF PK model of ceftriaxone, using not only serum but also CSF concentration data, and to evaluate the appropriateness of dosing regimens for pediatric patients with bacterial meningitis. Methods. The population PK model was developed by simultaneously fitting serum and CSF data from pediatric patients described in nine published articles. Probabilities of attaining a pharmacodynamic target (100% T > MIC, 100% of time that drug concentrations above the minimum inhibitory concentration) in CSF were estimated for some dosing regimens. Results and Discussion. Twenty-four pediatric patients with meningitis were the subjects for PK modeling (0.52–13 years old, and 3.5–50 kg of body weight). Sixty-eight serum concentrations and 98 CSF samples were used to develop the CSF PK model. The CSF/serum concentration ratio at the same sampling time was 0.0628 ± 0.0689. Age was not a statistically significant covariate in the PK parameter. In the CSF PK model, 40–60 mg/kg q12 h achieved a target attainment probability >90% against causative bacteria for bacterial meningitis. However, 4-h infusion (rather than 0.5-h infusion) dosing regimens were required for efficacy against antimicrobial-resistant bacteria with high MICs. What Is New? and Conclusion. Ceftriaxone-dosing regimens with prolonged infusion times might be reasonably effective for treating antimicrobial-resistant pathogens in empiric therapy.
Conflicts of Interest
The authors declare that they have no conflicts of interest.
Open Research
Data Availability
The data supporting the findings of this study were derived from the resource available in the public domain.
References
- 1 Kim K. S., Acute bacterial meningitis in infants and children, The Lancet Infectious Diseases. (2010) 10, no. 1, 32–42, https://doi.org/10.1016/s1473-3099(09)70306-8, 2-s2.0-72149117409.
- 2 Sáez-Llorens X. and McCrackenG. H.Jr., Bacterial meningitis in neonates and children, Infectious Disease Clinics of North America. (1990) 4, 623–644, https://doi.org/10.1016/s0891-5520(20)30369-x.
- 3 Libster R., Edwards K. M., Levent F., Edwards M. S., Rench M. A., Castagnini L. A., Cooper T., Sparks R. C., Baker C. J., and Shah P. E., Long-term outcomes of group B streptococcal meningitis, Pediatrics. (2012) 130, no. 1, e8–e15, https://doi.org/10.1542/peds.2011-3453, 2-s2.0-84863508160.
- 4 Stockmann C., Ampofo K., Byington C. L., Filloux F., Hersh A. L., Blaschke A. J., Cowan P., Korgenski K., Mason E. O., and Pavia A. T., Pneumococcal meningitis in children: epidemiology, serotypes, and outcomes from 1997-2010 in Utah, Pediatrics. (2013) 132, no. 3, 421–428, https://doi.org/10.1542/peds.2013-0621, 2-s2.0-84884556901.
- 5 Yogev R. and Guzman-Cottrill J., Bacterial meningitis in children: critical review of current concepts, Drugs. (2005) 65, no. 8, 1097–1112, https://doi.org/10.2165/00003495-200565080-00005, 2-s2.0-20544460403.
- 6 Li C., Feng W. Y., Lin A. W., Zheng G., Wang Y. C., Han Y. J., Zhong J. M., Bi J., Luo Q., Zhao F. C., Jin P., Guo L. Y., Li N., Yu J., Yang X. T., Liang J., Deng J. K., Li Y. J., Wang Y. J., Yu X. Y., Wang D. M., Ru L., Chen J., Yang Y. H., Yang Q. Z., and Liu G., Clinical characteristics and etiology of bacterial meningitis in Chinese children >28 days of age, January 2014-December 2016: a multicenter retrospective study, International Journal of Infectious Diseases. (2018) 74, 47–53, https://doi.org/10.1016/j.ijid.2018.06.023, 2-s2.0-85051145411.
- 7
Assegu Fenta D.,
Lemma K.,
Tadele H.,
Tadesse B. T., and
Derese B., Antimicrobial sensitivity profile and bacterial isolates among suspected pyogenic meningitis patients attending at Hawassa University Hospital: cross-sectional study, Brihanmumbai Municipal Corporation Microbiology. (2020) 20, no. 1, https://doi.org/10.1186/s12866-020-01808-5.
10.1186/s12866-020-01808-5 Google Scholar
- 8 Chang B., Tamura K., Fujikura H., Watanabe H., Tanabe Y., Kuronuma K., Fujita J., Oshima K., Maruyama T., Abe S., Kasahara K., Nishi J., Kubota T., Kinjo Y., Serizawa Y., Shimbashi R., Fukusumi M., Shimada T., Sunagawa T., Suzuki M., Oishi K., Chang B., Tamura K., Fujikura H., Watanabe H., Tanabe Y., Kuronuma K., Fujita J., Oshima K., Maruyama T., Abe S., Kasahara K., Nishi J., Kubota T., Kinjo Y., Serizawa Y., Shimbashi R., Fukusumi M., Shimada T., Sunagawa T., Suzuki M., Oishi K., Gotoh K., Tsubata C., Takahashi H., Aoyagi T., Nakamatsu M., Imuta N., Yokoyama A., Takeda H., and Ishida M., Pneumococcal meningitis in adults in 2014-2018 after introduction of pediatric 13-valent pneumococcal conjugate vaccine in Japan, Scientific Reports. (2022) 12, no. 1, https://doi.org/10.1038/s41598-022-06950-w.
- 9 Usp, Ceftriaxone for injection and dextrose injection draft labeling text, 2023, https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/050796s014lbl.pdf.
- 10 Eu, Ceftriaxone summary of product characteristics, 2023, https://www.ema.europa.eu/en/documents/referral/rocephin-article-30-referral-annex-iii_en.pdf.
- 11 Taiyo Pharma Co Ltd, Rocephin (ceftriaxone for injection) prescribing information, 2022, https://www.info.pmda.go.jp/go/pack/6132419F1020_3_07/?view=frame&style=XML&lang=ja.
- 12 Craig W. A., Pharmacokinetic/pharmacodynamic parameters: rationale for antibacterial dosing of mice and men, Clinical Infectious Diseases. (1998) 26, no. 1, 11–12, https://doi.org/10.1086/516284.
- 13 Craig W. A., Does the dose matter?, Clinical Infectious Diseases. (2001) 33, no. s3, S233–S237, https://doi.org/10.1086/321854, 2-s2.0-0035885054.
- 14 Iida S., Kawanishi T., and Hayashi M., Indications for a ceftriaxone dosing regimen in Japanese paediatric patients using population pharmacokinetic/pharmacodynamic analysis and simulation, Journal of Pharmacy and Pharmacology. (2010) 63, no. 1, 65–72, https://doi.org/10.1111/j.2042-7158.2010.01179.x, 2-s2.0-78650407104.
- 15 Wang Y. K., Wu Y. E., Li X., Tian L. Y., Khan M. W., Tang B. H., Shi H. Y., Zheng Y., Hao G. X., van den Anker J., You D. P., and Zhao W., Optimal dosing of ceftriaxone in infants based on a developmental population pharmacokinetic-pharmacodynamic analysis, Antimicrobial Agents and Chemotherapy. (2020) 64, no. 11, e01412–e01420, https://doi.org/10.1128/aac.01412-20.
- 16 Hartman S. J. F., Upadhyay P. J., Hagedoorn N. N., Mathôt R. A. A., Moll H. A., van der Flier M., Schreuder M. F., Brüggemann R. J., Knibbe C. A., and de Wildt S. N., Current ceftriaxone dose recommendations are adequate for most critically Ill children: results of a population pharmacokinetic modeling and simulation study, Clinical Pharmacokinetics. (2021) 60, no. 10, 1361–1372, https://doi.org/10.1007/s40262-021-01035-9.
- 17 Tang Girdwood S., Dong M., Tang P., Stoneman E., Jones R., Yunger T., Ostermeier A., Curry C., Forton M., Hail T., Mullaney R., Lahni P., Punt N., Kaplan J., and Vinks A. A., Population pharmacokinetic modeling of total and free ceftriaxone in critically Ill children and young adults and Monte Carlo simulations support twice daily dosing for target attainment, Antimicrobial Agents and Chemotherapy. (2022) 66, no. 1, 142721, https://doi.org/10.1128/aac.01427-21.
- 18 Yoshizawa K., Ikawa K., Ikeda K., Ohge H., and Morikawa N., Population pharmacokinetic-pharmacodynamic target attainment analysis of imipenem plasma and urine data in neonates and children, The Pediatric Infectious Disease Journal. (2013) 32, no. 11, 1208–1216, https://doi.org/10.1097/inf.0b013e31829b5880, 2-s2.0-84886949173.
- 19 Onita T., Ikawa K., Ishihara N., Tamaki H., Yano T., Naora K., and Morikawa N., Pharmacodynamic evaluation of ampicillin-sulbactam in pediatric patients using plasma and urine data, The Pediatric Infectious Disease Journal. (2022) 41, no. 5, 411–416, https://doi.org/10.1097/inf.0000000000003496.
- 20 Nagamatsu I., Miyanosita A., and Abe K., Ceftriaxone therapy for pediatric infections, Japanese Journal of Antibiotics. (1984) 37, no. 11, 2003–2011.
- 21 Satoh Y., Iwata S., Akita H., Murai T., Hayano S., Oikawa T., and Osano M., Fundamental and clinical evaluation of ceftriaxone in the field of pediatrics, Japanese Journal of Antibiotics. (1984) 37, no. 11, 2034–2048.
- 22 Toyonaga Y., Kurosu Y., Uekusa T., Nakamura H., Sugita M., Okabe T., Kawamura K., Seo K., Takahashi T., and Hori M., Fundamental and clinical evaluation on ceftriaxone in the pediatric field, Japanese Journal of Antibiotics. (1984) 37, no. 11, 2060–2082.
- 23 Nakazawa S., Satoh H., Niino K., Hirama Y., Narita A., Suzuki H., Nakazawa S., Chikaoka H., and Tazoe K., Evaluation on ceftriaxone in the pediatric field, Japanese Journal of Antibiotics. (1984) 37, no. 11, 2083–2101.
- 24 Sunakawa K., Saitoh N., Adachibara A., Ishizuka Y., Iwata S., Satoh Y., and Akita H., Fundamental and clinical evaluation of ceftriaxone in the pediatric field, Japanese Journal of Antibiotics. (1984) 37, no. 11, 2102–2110.
- 25 Iwai N., Taneda Y., Shibata M., Mizoguchi F., and Katayama M., Fundamental and clinical evaluation of ceftriaxone in the pediatric field, Japanese Journal of Antibiotics. (1984) 37, no. 11, 2111–2130.
- 26 Haruta T., Kuroki S., Mayumi M., Matsuo H., Ohkura K., and Kobayashi Y., Clinical evaluation on ceftriaxone in the field of pediatrics, Japanese Journal of Antibiotics. (1984) 37, no. 11, 2141–2151.
- 27 Motohiro T., Tanaka K., Koga T., Shimada Y., Tomita N., Sakata Y., Nishiyama T., Ishimoto K., Tominaga K., Yamashita F., Kimura K., Takajo N., Yoshimoto M., Kinoshita S., Fujisawa T., Eguchi H., Imai S., Nagayama K., Yuasa T., Tsugawa S., Tanaka Y., Arai H., Ishikawa Y., Yamashita Y., Sakamoto H., Tanaka N., Kuda N., Ono E., Fujimoto T., Katafuchi Y., Iriki T., Harada M., Yamamoto M., Komatsu Y., Tanaka C., Matsunaga S., Matsuura S., Fujimatsu M., Harada Y., Ohta M., Matsuo H., Yuge K., Kimura Y., Tanaka E., Dai S., Urabe D., and Kajiyama J., Fundamental and clinical evaluation of ceftriaxone in the pediatric field, Japanese Journal of Antibiotics. (1984) 37, no. 11, 2152–2168.
- 28 Okura K., Yamamoto H., Yamaoka K., Kubo K., Mitsuyoshi I., Haruta T., and Kobayashi Y., Clinical evaluation of ceftriaxone in the treatment of neonatal infections, Japanese Journal of Antibiotics. (1988) 41, no. 2, 152–164.
- 29 Lindbom L., Ribbing J., and Jonsson E. N., Perl-speaks-NONMEM (PsN)—a Perl module for NONMEM related programming, Computer Methods and Programs in Biomedicine. (2004) 75, no. 2, 85–94, https://doi.org/10.1016/j.cmpb.2003.11.003, 2-s2.0-2942744625.
- 30 Eucast, The European committee on antimicrobial susceptibility testing- EUCAST, 2022, http://mic.eucast.org/Eucast2/.
- 31 Latif R. and Dajani A. S., Ceftriaxone diffusion into cerebrospinal fluid of children with meningitis, Antimicrobial Agents and Chemotherapy. (1983) 23, no. 1, 46–48, https://doi.org/10.1128/aac.23.1.46, 2-s2.0-0020700639.
- 32 Steele R. W., Eyre L. B., Bradsher R. W., Weinfeld R. E., Patel I. H., and Spicehandler J., Pharmacokinetics of ceftriaxone in pediatric patients with meningitis, Antimicrobial Agents and Chemotherapy. (1983) 23, no. 2, 191–194, https://doi.org/10.1128/aac.23.2.191, 2-s2.0-0020676149.
- 33 Schaad U. B. and Stoeckel K., Single-dose pharmacokinetics of ceftriaxone in infants and young children, Antimicrobial Agents and Chemotherapy. (1982) 21, no. 2, 248–253, https://doi.org/10.1128/aac.21.2.248, 2-s2.0-0020040001.
- 34 Del Rio M., McCrackenG. H.Jr., Nelson J. D., Chrane D., and Shelton S., Pharmacokinetics and cerebrospinal fluid bactericidal activity of ceftriaxone in the treatment of pediatric patients with bacterial meningitis, Antimicrobial Agents and Chemotherapy. (1982) 22, no. 4, 622–627, https://doi.org/10.1128/aac.22.4.622, 2-s2.0-0020449995.
- 35 Khan M. W., Wang Y. K., Wu Y. E., Tang B. H., Kan M., Shi H. Y., Zheng Y., Xu B. P., Shen A. D., Jacqz-Aigrain E., Tian L. Y., and Zhao W., Population pharmacokinetics and dose optimization of ceftriaxone for children with community-acquired pneumonia, European Journal of Clinical Pharmacology. (2020) 76, no. 11, 1547–1556, https://doi.org/10.1007/s00228-020-02939-4.
- 36 Martin E., Koup J. R., Paravicini U., and Stoeckel K., Pharmacokinetics of ceftriaxone in neonates and infants with meningitis, The Journal of Pediatrics. (1984) 105, no. 3, 475–481, https://doi.org/10.1016/s0022-3476(84)80032-3, 2-s2.0-0021267286.
- 37 McCrackenG. H.Jr., Siegel J. D., Threlkeld N., and Thomas M., Ceftriaxone pharmacokinetics in newborn infants, Antimicrobial Agents and Chemotherapy. (1983) 23, no. 2, 341–343, https://doi.org/10.1128/aac.23.2.341, 2-s2.0-0020691108.
- 38 Societas Neurologica Japonica, Practical Guideline for Bacterial Meningitis 2014, 2014, Japanese Society of Neurological Therapeutics, Japanese Society for Neuroinfectious Diseases, Tokyo, Japan.
- 39 Gilbert D. N., Chambers H. F., Saag M. S., Pavia A., Boucher H. W., and Sanford J. P., The Sanford Guide to Antimicrobial Therapy, 2021, 51th edition, Sanford Guide, Sperryville, VA, USA.
- 40 Ubukata K., Chiba N., Morozumi M., Iwata S., and Sunakawa K., Longitudinal surveillance of Haemophilus influenzae isolates from pediatric patients with meningitis throughout Japan, 2000–2011, Journal of Infection and Chemotherapy. (2013) 19, no. 1, 34–41, https://doi.org/10.1007/s10156-012-0448-x, 2-s2.0-84874111308.
- 41
Schaad U. B.,
Wedgwood-Krucko J., and
Tschaeppeler H., Reversible ceftriaxone-associated biliary pseudolithiasis in children, The Lancet. (1988) 332, no. 8625, 1411–1413, https://doi.org/10.1016/s0140-6736(88)90596-x, 2-s2.0-0024243557.
10.1016/S0140-6736(88)90596-X Google Scholar
- 42 Schaad U. B., Tschäppeler H., and Lentze M. J., Transient formation of precipitations in the gallbladder associated with ceftriaxone therapy, The Pediatric Infectious Disease Journal. (1986) 5, no. 6, 708–709, https://doi.org/10.1097/00006454-198611000-00026.
- 43 Robertson F. M., Crombleholme T. M., Barlow S. E., Verhave M., and Brown D., Ceftriaxone choledocholithiasis, Pediatrics. (1996) 98, no. 1, 133–135, https://doi.org/10.1542/peds.98.1.133.
- 44 Lopez A. J., O’Keefe P., Morrissey M., and Pickleman J., Ceftriaxone-induced cholelithiasis, Annals of Internal Medicine. (1991) 115, no. 9, 712–714, https://doi.org/10.7326/0003-4819-115-9-712, 2-s2.0-0026063322.
- 45 Zinberg J., Chernaik R., Coman E., Rosenblatt R., and Brandt L. J., Reversible symptomatic biliary obstruction associated with ceftriaxone pseudolithiasis, American Journal of Gastroenterology. (1991) 86, no. 9, 1251–1254.
- 46 Jacobs R. F., Ceftriaxone-associated cholecystitis, The Pediatric Infectious Disease Journal. (1988) 7, no. 6, 434–435, https://doi.org/10.1097/00006454-198806000-00018.
- 47 Maranan M. C., Gerber S. I., and Miller G. G., Gallstone pancreatitis caused by ceftriaxone, The Pediatric Infectious Disease Journal. (1998) 17, no. 7, 662–663, https://doi.org/10.1097/00006454-199807000-00022, 2-s2.0-0031874256.