Pharmacokinetics and Safety of Levofloxacin for Treatment of Rifampicin-Resistant Tuberculosis During Pregnancy and the Postpartum Period: Results from IMPAACT P1026s

Jennifer A Hughes¹, Mauricio Pinilla², Kristina M Brooks³, Ahizechukwu C Eke⁴, Alice Stek⁵, Brookie M Best⁶, Mark Mirochnick⁷, Renee Browning⁸, Lubbe Wiesner⁹, Kathleen George¹⁰, Kevin Knowles¹¹, Petra De Koker¹², James S Ngocho¹³, Lee Fairlie¹⁴, Nahida Chakhtoura¹⁵, Anneke C Hesseling¹², Eric Decloedt¹⁶, David E Shapiro², Marije van Schalkwyk¹⁷; IMPAACT P1026s Protocol Team

Affiliations

¹ Desmond Tutu TB Centre, Department of Paediatrics and Child Health, Faculty of Medicine and Health Sciences, Stellenbosch University, Francie van Zijl Drive, Tygerberg, Cape Town, 7505, South Africa. jhughes@sun.ac.za.
² Center for Biostatistics in AIDS Research, Harvard T. H. Chan School of Public Health, Boston, MA, USA.
³ Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
⁴ Department of Gynecology and Obstetrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁵ Department of Obstetrics and Gynecology, University of Southern California School of Medicine, Los Angeles, CA, USA.
⁶ Division of Clinical Pharmacy and Department of Pediatrics, University of California San Diego Skaggs School of Pharmacy and Pharmaceutical Sciences and School of Medicine-Rady Children's Hospital San Diego, San Diego, CA, USA.
⁷ Division of Neonatology, Department of Pediatrics, Boston University Chobanian and Avedisian School of Medicine, Boston, MA, USA.
⁸ National Institutes of Health, National Institute of Allergy and Infectious Diseases, Bethesda, MD, USA.
⁹ Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa.
¹⁰ FHI 360, Durham, NC, USA.
¹¹ Frontier Science Foundation, Amherst, NY, USA.
¹² Desmond Tutu TB Centre, Department of Paediatrics and Child Health, Faculty of Medicine and Health Sciences, Stellenbosch University, Francie van Zijl Drive, Tygerberg, Cape Town, 7505, South Africa.
¹³ Department of Epidemiology and Applied Biostatistics, Kilimanjaro Christian Medical University College, Moshi, Tanzania.
¹⁴ Wits RHI, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
¹⁵ Maternal and Pediatric Infectious Disease Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), Bethesda, MD, USA.
¹⁶ Division of Clinical Pharmacology, Department of Medicine, Tygerberg Hospital, Stellenbosch University, Cape Town, South Africa.
¹⁷ Division of Adult Infectious Diseases, Department of Medicine, Family Centre for Research with Ubuntu, Stellenbosch University and Tygerberg Hospital, Francie van Zijl Drive, Tygerberg, Cape Town, 7505, South Africa. marije@sun.ac.za.

PMID: 40155501
PMCID: PMC12041113
DOI: 10.1007/s40262-025-01498-0

Observational Study

Pharmacokinetics and Safety of Levofloxacin for Treatment of Rifampicin-Resistant Tuberculosis During Pregnancy and the Postpartum Period: Results from IMPAACT P1026s

Jennifer A Hughes et al. Clin Pharmacokinet. 2025 Apr.

. 2025 Apr;64(4):619-630.

doi: 10.1007/s40262-025-01498-0. Epub 2025 Mar 28.

Authors

Affiliations

¹ Desmond Tutu TB Centre, Department of Paediatrics and Child Health, Faculty of Medicine and Health Sciences, Stellenbosch University, Francie van Zijl Drive, Tygerberg, Cape Town, 7505, South Africa. jhughes@sun.ac.za.
² Center for Biostatistics in AIDS Research, Harvard T. H. Chan School of Public Health, Boston, MA, USA.
³ Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
⁴ Department of Gynecology and Obstetrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁵ Department of Obstetrics and Gynecology, University of Southern California School of Medicine, Los Angeles, CA, USA.
⁶ Division of Clinical Pharmacy and Department of Pediatrics, University of California San Diego Skaggs School of Pharmacy and Pharmaceutical Sciences and School of Medicine-Rady Children's Hospital San Diego, San Diego, CA, USA.
⁷ Division of Neonatology, Department of Pediatrics, Boston University Chobanian and Avedisian School of Medicine, Boston, MA, USA.
⁸ National Institutes of Health, National Institute of Allergy and Infectious Diseases, Bethesda, MD, USA.
⁹ Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa.
¹⁰ FHI 360, Durham, NC, USA.
¹¹ Frontier Science Foundation, Amherst, NY, USA.
¹² Desmond Tutu TB Centre, Department of Paediatrics and Child Health, Faculty of Medicine and Health Sciences, Stellenbosch University, Francie van Zijl Drive, Tygerberg, Cape Town, 7505, South Africa.
¹³ Department of Epidemiology and Applied Biostatistics, Kilimanjaro Christian Medical University College, Moshi, Tanzania.
¹⁴ Wits RHI, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
¹⁵ Maternal and Pediatric Infectious Disease Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), Bethesda, MD, USA.
¹⁶ Division of Clinical Pharmacology, Department of Medicine, Tygerberg Hospital, Stellenbosch University, Cape Town, South Africa.
¹⁷ Division of Adult Infectious Diseases, Department of Medicine, Family Centre for Research with Ubuntu, Stellenbosch University and Tygerberg Hospital, Francie van Zijl Drive, Tygerberg, Cape Town, 7505, South Africa. marije@sun.ac.za.

PMID: 40155501
PMCID: PMC12041113
DOI: 10.1007/s40262-025-01498-0

Abstract

Background and objective: Treatment of rifampicin-resistant tuberculosis (RR-TB) often includes fluoroquinolones, but data on long-term exposure during and after pregnancy are limited. We examined the pharmacokinetics and safety of levofloxacin in an observational cohort of pregnant and postpartum women receiving treatment for RR-TB.

Methods: Participants were enrolled in their second or third trimester and underwent intensive pharmacokinetic sampling to quantify levofloxacin plasma concentrations at 20-26 weeks' and 30-38 weeks' gestation and at 2-8 weeks postpartum. The levofloxacin plasma concentration target was 7 µg/mL. Pharmacokinetic parameters over 12 and 24 h were described using non-compartmental analysis and within-participant comparison during pregnancy versus postpartum. Adverse events were extracted from medical records. Infants were enrolled in utero and followed on study for 4-6 months after birth.

Results: A total of 11 pregnant women, with a median age of 31 years, received RR-TB treatment including levofloxacin; 6 (55%) were living with HIV. In the second trimester, third trimester, and postpartum, median maximum plasma drug concentration values were 10.3, 10.6, and 10.6 µg/mL, and area under the concentration time curve over 12 h (AUC_0-12) were 69.0, 77.6, and 80.2 µg·h/mL, respectively. Compared with postpartum, median AUCs were lower and clearance was higher in the second but not the third trimester. Eight (72%) women and seven (64%) infants experienced severe or life-threatening adverse events or outcomes that were unlikely to be related to levofloxacin.

Conclusions: Levofloxacin AUC_0-12 was lower in the second trimester than the third trimester of pregnancy and the postpartum period, but exposures overall were within target ranges. Further research is warranted to explore the clinical significance of these findings.

PubMed Disclaimer

Conflict of interest statement

Declarations. Funding: Open access funding provided by Stellenbosch University. Overall support for the International Maternal Pediatric Adolescent AIDS Clinical Trials Network (IMPAACT) was provided by the National Institute of Allergy and Infectious Diseases with co-funding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) and the National Institute of Mental Health, all components of the National Institutes of Health, under award numbers UM1AI068632 (IMPAACT LOC), UM1AI068616 (IMPAACT SDMC), and UM1AI106716 (IMPAACT LC), and by NICHD contract number HHSN275201800001I. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The University of Cape Town Clinical PK Laboratory has been granted funding as an International Pharmacology Specialty Laboratory by the IMPAACT network. Conflicts of Interest: The authors have no conflicts of interest to declare. Ethics Approval: Ethics review board approvals for the IMPAACT P1026s study were received from the Stellenbosch University Health Research Ethics Committee (N13/02/025_DTTC; 24 November 2016) and the University of the Witwatersrand Human Research Ethics Committee: Medical (160913; 24 March 2017). This study was performed in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. Consent to Participate: All pregnant participants provided written informed consent for themselves and their infants to take part in this study. Consent for Publication: Not applicable (data are presented in aggregate and no personally identifiable information has been included in this manuscript). Author’s Contributions: AS, BMB, MM, and DES contributed to the conceptualisation of the study and study design. RB, KG and NC contributed to the study implementation and oversight. PDK, LW, JSN, and LF contributed to the study implementation, data collection, and sample processing at the highest enrolling study sites. JH and ACE contributed to the literature search for the manuscript. KK contributed to the data extraction. JH, MP, KMB, DES, and MvS contributed to the data analysis. JH, ACE, ACH, and ED contributed to the writing of the manuscript. All authors contributed to reviewing the manuscript, and all authors have read and approved the final version. Data Availability: The data that support the findings of this study cannot be made publicly available because of the ethical restrictions in the study’s informed consent documents and in the International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) Network’s approved human subjects protection plan; public availability may compromise participant confidentiality. However, data are available to all interested researchers upon reasonable request to the IMPAACT Statistical and Data Management Center’s data access committee (email: sdac.data@fstrf.org) with the agreement of the IMPAACT Network.

Figures

**Fig. 1**
Mean (standard deviation) plasma levofloxacin concentration–time profiles through 12 h after dose by trimester

**Fig. 2**
Box-and-whisker plots of A levofloxacin area under the concentration time curve from 0 to 24 h (AUC_0–24) and B levofloxacin maximum plasma drug concentration (C_max), by trimester. Grey shading indicates typical values measured in non-pregnant adults [16]. The dotted line on (B) indicates the minimum target of 7 µg/mL

See this image and copyright information in PMC

References

1. WHO. World Health Organization. Global tuberculosis report 2023. Geneva, Switzerland: WHO. 2023. https://www.who.int/teams/global-tuberculosis-programme/data, accessed 27 Nov 2023; 2023.
1. World Health Organization. WHO consolidated guidelines on tuberculosis. Module 4: treatment - drug-resistant tuberculosis treatment, 2022 update. Geneva, Switzerland: WHO. 2022. https://www.who.int/publications/i/item/9789240063129 (Accessed on 22 Jul 2023); 2022.
1. World Health Organization. Rapid communication: key changes to treatment of multidrug- and rifampicin-resistant tuberculosis (MDR/RR-TB), August 2018. Licence: CC BY-NC-SA 3.0 IGO. Geneva, Switzerland: WHO. 2018. https://www.who.int/publications/i/item/WHO-CDS-TB-2018.18 (Accessed 04 Oct 2023); 2018.
1. Collaborative Group for the Meta-Analysis of Individual Patient Data in MDRTBt, Ahmad N, Ahuja SD, et al. Treatment correlates of successful outcomes in pulmonary multidrug-resistant tuberculosis: an individual patient data meta-analysis. Lancet. 2018;392(10150):821–34. - PMC - PubMed
1. Maugans C, Loveday M, Hlangu S, et al. Best practices for the care of pregnant people living with TB. Int J Tuberc Lung Dis. 2023;27(5):357–66. - PMC - PubMed

Publication types

Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

Pharmacokinetics and Safety of Levofloxacin for Treatment of Rifampicin-Resistant Tuberculosis During Pregnancy and the Postpartum Period: Results from IMPAACT P1026s

Affiliations

Pharmacokinetics and Safety of Levofloxacin for Treatment of Rifampicin-Resistant Tuberculosis During Pregnancy and the Postpartum Period: Results from IMPAACT P1026s

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Medical