An Observational Study on the Pharmacokinetics of Levofloxacin in Lactating Atypical Pneumonia Patients

Abstract

Importance:

Atypical pneumonia in postpartum women may alter drug pharmacokinetics (PK) through cytokine-mediated changes in vascular permeability, yet the breast milk disposition of levofloxacin in this population remains uncharacterized.

Objective:

This observational study aimed to compare levofloxacin PK in lactating atypical pneumonia patients (n = 10) receiving 400 mg once daily for 3 days with historical healthy controls and to assess infant exposure risks.

Methods:

Breast milk samples from subjects 6–10 were collected at predetermined time points (0.5, 1, 2, 4, 6, 8, 10, 12, and 24 hours) following the last dose of 3 days. Subjects 1–5 had random daytime sampling. The concentration of levofloxacin in breast milk was measured using a validated high-performance liquid chromatography method with ultraviolet detection (correlation coefficient: 0.9997; limit of detection: 0.15 μg/mL; recovery: 91.36–102.28%; RSD <5%). PK parameters were derived using noncompartmental analysis in Phoenix WinNonlin (version 8.35).

Results:

Key milk PK parameters included C_max of subjects 1–5 was 15.74 ± 6.55 μg/mL, and in subjects 6–10 was 14.55 ± 2.56 μg/mL. The elimination half-life (t_1/2β) in subjects 1–5 was 7.46 ± 3.39 hours and in subjects 6–10 was 4.57 ± 1.14 hours. The AUC₀₋₂₄ in subjects 1–5 was 84.31 ± 22.60 mg·h/L and in subjects 6–10 was 63.99 ± 11.78 mg·h/L.

Conclusions:

Based on a 150 mL/kg/day milk intake, the estimated infant daily exposure in subjects 1–5 and 6–10 was 0.53 ± 0.14 and 0.40 ± 0.07 μg/kg/day, respectively, which was below 10% of the therapeutic dose (10 mg/kg once daily) for infants aged 0–12 months. This study first quantified levofloxacin in atypical pneumonia patients’ breast milk using a validated method. Results suggest that breastfeeding can continue cautiously during maternal levofloxacin therapy. Avoid breastfeeding at peak drug concentration and monitor the infant for potential reactions.

Introduction

Atypical pneumonia in lactating women represents a significant public health concern due to heightened risks of severe complications, including hospitalization and maternal mortality.^1–3 Physiological adaptations during lactation, such as increased cardiac output and altered immune responses, may exacerbate susceptibility to respiratory pathogens.^4,5 Despite the clinical necessity of antibiotics like levofloxacin for treating bacterial co-infections in atypical pneumonia, critical gaps persist in understanding its pharmacokinetic (PK) behavior in breast milk. Current guidelines rely on extrapolated data from nonlactating populations, ignoring lactation-specific factors such as maternal drug transporters, pH-dependent milk partitioning, and dynamic changes in milk composition over time.^6–8 This paucity of data leaves clinicians navigating an ethical and therapeutic dilemma: balancing the urgency of maternal treatment against potential risks to breastfeeding infants. Given that atypical pneumonia induced cytokine storms may alter drug distribution via increased vascular permeability, we hypothesized that levofloxacin PK in breast milk would differ between infected and healthy lactating women.

Breastfeeding remains the gold standard for infant nutrition, conferring unparalleled immunological, developmental, and psychological benefits.^9–11 However, maternal antibiotic use during lactation introduces complex trade-offs. While untreated infections jeopardize maternal health and breastfeeding continuity, drug transfer into milk raises concerns about infant toxicity, gut microbiome disruption, and theoretical risks of fluoroquinolone-induced arthropathy.^12–14 Levofloxacin, a third-generation fluoroquinolone targeting DNA gyrase and topoisomerase IV, exhibits broad-spectrum activity against common respiratory pathogens but lacks comprehensive lactation safety data.^15–17 Existing studies, primarily limited to administrations in healthy postpartum women, fail to reflect real-world scenarios where atypical pneumonia patients require regimens.^18,19 Fever, dehydration, and cytokine-driven metabolic changes in atypical pneumonia may further alter levofloxacin’s absorption, volume of distribution, and renal clearance, potentially elevating milk concentrations beyond historical estimates.^20–22

This study aims to address these critical gaps by evaluating the PK characteristics of levofloxacin in lactating women with atypical pneumonia. Specifically, we will measure levofloxacin concentrations in breast milk following multiple doses, calculate the estimated daily infant exposure, and assess whether these levels fall within established safety thresholds. By providing these data, we will seek to inform evidence-based recommendations for levofloxacin use in this population, enabling clinicians to optimize maternal treatment while minimizing risks to breastfeeding infants. This research will contribute to a safer and more effective approach to managing atypical pneumonia in lactating women, ultimately supporting both maternal health and the continuation of breastfeeding.

Materials and Methods

Study design

This prospective observational clinical trial was conducted in the Department of Pharmacy, Maternal and Child Health of Hubei Province, Tongji Medical College, Huazhong University of Science and Technology. The study protocol was approved by the Institutional Review Board of Department of Hubei Maternal and Child Health Hospital, Huazhong University of Science and Technology (2024-030-01) and was conducted in accordance with the Helsinki Declaration.

Participant inclusion criteria: lactating women ≥18 years with PCR-confirmed atypical pneumonia; prescribed intravenous levofloxacin 400 mg q24h as monotherapy; postpartum period 14–365 days; willing to provide timed breast milk samples.

Participant exclusion criteria: renal impairment (estimated glomerular filtration rate <60 mL/min/1.73 m², Cockcroft–Gault equation); use of other antibiotics during the intravenous infusion of levofloxacin; breast milk production <100 mL/day. All participants provided written informed consent after receiving counseling on drug excretion into breast milk. All recruited patients signed a written informed consent form.

Patients received levofloxacin lactate and sodium chloride injection (200 mg levofloxacin per injection), kindly supplied by Zhejiang Pharmaceutical Co., Ltd. Xin Chang Pharmaceutical Factory (Shaoxing, China) prepared in the pharmacy at a standard dose of 400 mg once daily. Breast milk samples were obtained at 0.5, 1, 2, 4, 6, 8, 10, 12, and 24 hours following the last dose of 3 days and stored in tubes at a temperature not exceeding −80°C until use.

Analytical measurements

Levofloxacin concentrations in breast milk were quantified using a validated high-performance liquid chromatography (HPLC) method with ultraviolet (UV) detection. The HPLC system was equipped with a Cosmasil C18 (5 μm, 4.6 × 250 mm) column. The column temperature was 30°C, and the injection volume was 20 μL. Elution was performed using 0.025 mol/L potassium dihydrogen phosphate buffer with 0.3% triethylamine and 1% glacial acetic acid solution (mobile phase A) and acetonitrile (mobile phase B). The isocratic condition was 19% A and 81% B. The total run time was 10 minutes with 1 mL/min. The detection wavelength was set to 294 nm, with a retention time of 6.1 minutes for levofloxacin.

Breast milk samples underwent protein precipitation using methanol (1:1), followed by centrifugation at 2250 × g for 15 minutes. Supernatants were filtered through 0.22-μm nylon filters and placed in an automatic injection analysis vial. An aliquot of 20 μL was analyzed. Calibration curves were linear over 0.3125–20 μg/mL. The calibration curve equations of levofloxacin were A = 21.386C + 2.3889, showing a correlation coefficient of 0.9997, with intra- and inter-day precision (relative standard deviation, RSD) <4% and accuracy (relative error, RE) within ±10%. RSD values of the stability of the 4-hour post-treatment assay, stored at 4°C for 12 hours, repeated freezing and thawing 3 times, and stored at −80°C for 3 months were obtained between the range of 1.08–4.65%. The limit of detection (LOD) was 0.15 μg/mL. Quality control samples (0.3125, 1.25, and 5.0 μg/mL) were analyzed in six copies with each batch to ensure reproducibility.

Average consumption calculation for infants

Regression analysis was performed using levofloxacin peak area (A) as the vertical coordinate and mass concentration (C) as the horizontal coordinate. The peak area from each injection was substituted into the regression equation to calculate the corresponding concentration. The area under the curve (AUC) was calculated using the linear trapezoidal rule. AUC_0–24 provides an index of the total systemic exposure to the drug over the 24-hour observational period its appearance in breast milk and likely exposure to nursing infants. The average concentration of levofloxacin in breast milk was calculated based on the following equation.²³ $C_{breast milk, av} (μg / mL) = {AUC}_{breast milk 0 - 24h} (mg \cdot h / L) / 24 h$

The daily dose of levofloxacin for infants was estimated based on the average levofloxacin concentration in breast milk and the estimated daily breast milk consumption of exclusively breastfed infants.²⁴ $Infant dose (μg / kg / day) = C_{breast milk av} * 150 mL / kg / day$

The relative infant dose (RID) is a PK parameter used to estimate the exposure of a breastfed infant to a medication transferred via maternal milk. It is expressed as a percentage of the maternal dose normalized by body weight. Maternal dose is the mother’s dose normalized by her body weight.²⁵ $Maternal dose = total maternal dose (mg / day) / maternal weight (kg)$ $RID (%) = infant dose via breast milk (mg / kg / day) / maternal dose (mg / kg / day) * 100 %$

Statistical analysis

PK parameters were derived using noncompartmental analysis (NCA) in Phoenix WinNonlin (version 8.35). The PK parameters included the maximum concentration in human breast milk (C_max), the time to reach the C_max (T_max), the elimination half-life (t_1/2), and the area under the breast milk concentration-time curve from the time of dosing to 24 hours (AUC₀₋₂₄). A breast milk concentration-time curve was plotted based on the concentration of levofloxacin in breast milk.

Results

Ten women who were breastfeeding or had just given birth and had been diagnosed with atypical pneumonia were enrolled in the present study. We analyzed their levofloxacin PK parameters following a regular dosage of 400 mg of levofloxacin once daily. At the beginning of the study, limited funding and poor patient compliance resulted in breast milk samples from patients 1–5 not adhering to this strict sampling schedule. Instead, their milk samples were collected at random times during the day. In contrast, breast milk samples from subjects 6–10 were collected at predetermined time points (0.5, 1, 2, 4, 6, 8, 10, 12, and 24 hours) following the last dose over a period of 3 days. This resulted in differences in PK parameters between patients 1–5 and 6–10. In our study, the C_max of levofloxacin in the breast milk of subjects 1–5 was 15.74 ± 6.55 μg/mL and in subjects 6–10 was 14.55 ± 2.56 μg/mL. The half-life in subjects 1–5 was 7.46 ± 3.39 hours and subjects 6–10 was 4.57 ± 1.14 hours. The AUC₀₋₂₄ of levofloxacin in subjects 1–5 was 84.31 ± 22.60 mg·h/L and in subjects 6–10 was 63.99 ± 11.78 mg·h/L. The PK parameters Cmax, Tmax, t_1/2, and AUC₀₋₂₄ are shown in Table 1. The concentration-time profiles of levofloxacin in breast milk for subjects 1–5 are plotted in Figure 1. The concentration-time profiles of levofloxacin in breast milk for subjects 6–10 are shown in Figure 2.

FIG. 1.

Levofloxacin concentration in breast milk of subjects 1–5.

FIG. 2.

Levofloxacin concentration in breast milk of subjects 6–10.

Table 1.

Pharmacokinetic Parameters of Levofloxacin in Breast Milk

Subject	T_max (hours)	C_max (µg/mL)	T_1/2 (hours)	AUC₀₋₂₄ (mg·h/L)
1	1.00	14.28	10.85	95.32
2	2.33	9.19	4.07	61.71
3	2.00	11.02	5.97	102.96
4	2.50	12.24	4.15	101.89
5	0.33	22.28	4.31	106.91
6	0.50	11.99	4.54	52.21
7	0.50	13.78	3.56	75.77
8	0.50	14.53	5.27	60.22
9	0.50	13.43	5.71	58.92
10	0.50	17.11	3.43	68.59

Based on the measured levofloxacin concentrations in the breast milk, the average concentrations were calculated to estimate the daily exposure to levofloxacin for exclusively breastfed infants based on their daily milk consumption. The calculated daily exposure to subjects 1–5 and subjects 6–10 was 0.53 ± 0.14 and 0.40 ± 0.07 μg/kg/day, respectively, for exclusively breastfed infants, which is <10% of the recommended therapeutic dose for 0 to 12-month-old infants (10 mg/kg once daily). The RID of subjects 1–5 was 8.15 ± 1.56% and of subjects 6–10 was 6.11 ± 1.41%. The data on the RID of levofloxacin are given in Table 2.

Table 2.

The Data on the Relative Infant Dose of Levofloxacin

Subject	Weight (kg)	Infant dose (mg/kg/day)	AUC₀₋₂₄ (mg·h/L)	RID (%)
1	62.5	0.60	95.32	9.31
2	68.3	0.39	61.71	6.59
3	59.7	0.64	102.96	9.60
4	55.2	0.64	101.89	8.79
5	58.1	0.67	106.91	9.71
6	57.6	0.33	52.21	4.70
7	63.4	0.47	75.77	7.51
8	56.3	0.38	60.22	5.30
9	61.7	0.37	58.92	5.68
10	57.2	0.43	68.59	6.13

Discussion

Study overview and key findings

This study provides the first detection of levofloxacin in breast milk using HPLC-UV and comprehensive PK data on levofloxacin in breast milk after intravenous levofloxacin administration from postpartum patients with atypical pneumonia. Our findings reveal two critical insights: (1) atypical pneumonia infection significantly increases levofloxacin exposure in breast milk compared with healthy postpartum women, and (2) despite this increase, the estimated daily exposure for exclusively breastfed infants remains below therapeutic thresholds, supporting cautious continuation of breastfeeding during maternal treatment.

In our study, we investigated the PK parameters of levofloxacin in 10 postpartum patients with atypical pneumonia who received a standard dose of 400 mg intravenously once daily. Cahill et al. reported a C_max of 8.2 μg/mL in a lactating patient following a single 500 mg IV administration.²⁶ The half-life in this patient was 7.0 hours, and the AUC₀₋₂₄ was 120 mg·h/L, which aligns with our findings. In contrast, Toker et al. found a much lower C_max of 0.26 ± 0.01 μg/mL in healthy postpartum subjects after a single oral 500 mg dose.¹⁹ This significant disparity may be attributed to differences in administration routes and patient conditions.

Levofloxacin exhibits high oral bioavailability, reaching up to 99%, indicating it can achieve effective concentrations in plasma and tissues regardless of the administration route. In healthy subjects, the C_max values for single and multiple oral doses of 500 mg levofloxacin were 5.1 ± 0.8 μg/mL and 5.7 ± 1.4 μg/mL, respectively. For single and multiple intravenous doses of 500 mg levofloxacin, the C_max values were 6.2 ± 1.0 μg/mL and 6.4 ± 0.8 μg/mL, respectively.²⁷ The concentration of levofloxacin in breast milk after oral administration of 500 mg of levofloxacin is comparable with that achieved with the intravenous administration of the same dose. Therefore, we conclude that the higher levofloxacin concentration in breast milk in patients compared with healthy subjects are mainly due to the physiological differences between the two groups.

Mechanistic insights into altered PK

Inflammatory cytokines, such as tumor necrosis factor-alpha and interleukins (IL-1β, IL-6, IL-8), disrupt the tight junctions between mammary epithelial cells. For instance, in a study by Wang et al., inflammatory responses induced by γ-D-glutamyl-meso-diaminopimelic acid led to tight junction disruption in bovine mammary epithelial cells.²⁸ This disruption increases the permeability of the mammary epithelial barrier, potentially allowing drugs to more readily cross into milk. As a result, patients may exhibit higher drug concentrations in their milk compared with healthy individuals.

Infant exposure risk assessment

Using the World Health Organization (WHO) recommended milk intake of 150 mL/kg/day, the calculated daily exposure to subjects 1–5 and subjects 6–10 was 0.53 ± 0.14 and 0.40 ± 0.07 μg/kg/day, respectively, for exclusively breastfed infants, which is <10% of the recommended therapeutic dose for 0 to 12-month-old infants (10 mg/kg once daily). These findings suggest that the estimated daily exposure to levofloxacin in breastfed infants is subtherapeutic and unlikely to cause direct toxicity.

However, two risks warrant attention: (1) Arthropathy: Fluoroquinolones are associated with cartilage damage in juvenile animal models, raising concerns about arthropathy in infants. While the exposure levels in our study (0.4–0.8 mg/kg/day) are below the therapeutic dose, the potential for dose-dependent and idiosyncratic arthropathy cannot be entirely ruled out.²⁹ (2) Microbiome disruption: Antibiotic exposure during infancy may alter gut microbiota composition, potentially increasing the risk of obesity, asthma, and atopy.^30–32 Levofloxacin’s broad-spectrum activity could theoretically exert similar effects via breast milk, as demonstrated by a study showing reduced microbial diversity in offspring exposed to low-dose ciprofloxacin in maternal milk.³³

Clinical implications and recommendations

Despite the subtherapeutic exposure levels, we recommend the following precautions to minimize potential risks: (1) Temporal avoidance: Waiting for 1 hour or longer after IV levofloxacin administration before resuming breastfeeding can avoid C_max, thereby reducing the infant dose. (2) Infant monitoring: Assess joint mobility weekly if maternal treatment exceeds 7 days. (3) Alternatives: For mild cases in high-risk infants, consider azithromycin (RID 2–4%), which has a safer profile in infants.

These measures balance the benefits of breastfeeding, as advocated by the WHO, with caution against fluoroquinolone class effects. Untreated maternal pneumonia poses higher risks to infants (28% hospitalization rate) compared with the theoretical 0.1% arthropathy risk from levofloxacin.^34,35

Limitations and future directions

Our study has several limitations that should be considered when interpreting the results. First, the lack of active metabolite measurement, desmethyl levofloxacin, limits the completeness of the PK profile. Second, the poor sampling of patients 1–5 affects the reliability of their data, while patients 6–10 likely provide more reliable data and the small sample size (n = 10) restricts the power of statistical analyses and the ability to perform subgroup comparisons. Third, the single-center design and the absence of infant outcome data limit the generalizability of the findings. Future research should focus on validating these PK models in larger, multicenter cohorts and assessing long-term microbiome and developmental outcomes in exposed infants. In addition, studies should explore the impact of maternal influenza severity on drug transfer into breast milk and the potential for alternative treatment options in this population.

Conclusion

For the first time, a rapid and simple HPLC-UV method for the quantification of levofloxacin in human breast milk was developed and validated. The sensitivity is sufficient to determine levofloxacin levels in human breast milk after intravenous administration. In addition, the developed method can be used easily and safely in laboratories. In conclusion, this study provides the first PK data on levofloxacin in breast milk from lactating women with atypical pneumonia. While the estimated infant exposure is below therapeutic thresholds, cautious monitoring and alternative treatment options should be considered to minimize potential risks. Future research should focus on validating these findings in larger cohorts and assessing long-term outcomes in exposed infants.

Footnotes

Acknowledgments

The authors express their gratitude to all contributors who played a role in this project but are not specifically acknowledged in the article.

Consent for Publication

All participants gave their consent to publish the data presented in this article.

Authors’ Contributions

J.S.: Conceptualization, methodology, writing—original draft preparation, writing—review and edit, validation. L.P.: Software, data curation, visualization. J.L.: Investigation, supervision. Y.L.: Software, article formatting correction. Y.L.: Conceptualization, methodology, writing—review, article formatting correction.

Disclosure Statement

No competing financial interests exist.

Funding Information

This study was not funded by any commercial or noncommercial body.

References

Laibl

, Sheffield

. Influenza and pneumonia in pregnancy. Clin Perinatol, 2005; 32(3):727–738; doi: 10.1016/j.clp.2005.04.009

Mathad

, Gupta

. Pulmonary infections in pregnancy. Semin Respir Crit Care Med, 2017; 38(2):174–184; doi: 10.1055/s-0037-1602375

Corica

, Tartaglia

, D’Amico

, et al. Sex and gender differences in community-acquired pneumonia. Intern Emerg Med, 2022; 17(6):1575–1588; doi: 10.1007/s11739-022-02999-7

Sanghavi

, Rutherford

. Cardiovascular physiology of pregnancy. Circulation, 2014; 130(12):1003–1008; doi: 10.1161/CIRCULATIONAHA.114.009029

Soma-Pillay

, Nelson-Piercy

, Tolppanen

, et al. Physiological changes in pregnancy. Cardiovasc J Afr, 2016; 27(2):89–94; doi: 10.5830/CVJA-2016-021

Ito

, Lee

. Drug excretion into breast milk—overview. Adv Drug Deliv Rev, 2003; 55(5):617–627; doi: 10.1016/S0169-409X(03)00034-6

Ilett

, Kristensen

. Drug use and breastfeeding. Expert Opin Drug Saf, 2005; 4(4):745–768; doi: 10.1517/14740338.4.4.745

McLeod

, Pullon

, Cookson

. Factors influencing continuation of breastfeeding in a cohort of women. J Hum Lact, 2002; 18(4):335–343; doi: 10.1177/089033402237906

Victora

, Bahl

, Barros

AJD

, et al.; Lancet Breastfeeding Series Group. Breastfeeding in the 21st century: Epidemiology, mechanisms, and lifelong effect. Lancet, 2016; 387(10017):475–490; doi: 10.1016/S0140-6736(15)01024-7

10.

Ballard

, Morrow

. Human milk composition: Nutrients and bioactive factors. Pediatr Clin North Am, 2013; 60(1):49–74; doi: 10.1016/j.pcl.2012.10.002

11.

Kramer

, Kakuma

. Optimal duration of exclusive breastfeeding. Cochrane Database Syst Rev, 2012; 2012(8):CD003517; doi: 10.1002/14651858.CD003517.pub2

12.

Nahum

, Uhl

, Kennedy

. Antibiotic use in pregnancy and lactation: What is and is not known about teratogenic and toxic risks. Obstet Gynecol, 2006; 107(5):1120–1138; doi: 10.1097/01.AOG.0000216197.26783.b5

13.

Patel

, Goldman

. Safety concerns surrounding quinolone use in children. J Clin Pharmacol, 2016; 56(9):1060–1075; doi: 10.1002/jcph.715

14.

Muanda

, Sheehy

, Bérard

. Use of antibiotics during pregnancy and risk of spontaneous abortion. CMAJ, 2017; 189(17):E625–E633; doi: 10.1503/cmaj.161020

15.

Une

, Fujimoto

, Sato

, et al. In vitro activity of DR-3355, an optically active ofloxacin. Antimicrob Agents Chemother, 1988; 32(9):1336–1340; doi: 10.1128/AAC.32.9.1336

16.

Davis

, Bryson

. Levofloxacin: A review of its antibacterial activity, pharmacokinetics and therapeutic efficacy. Drugs, 1994; 47(4):677–700; doi: 10.2165/00003495-199447040-00008

17.

Noreddin

, Elkhatib

. Levofloxacin in the treatment of community-acquired pneumonia. Expert Rev Anti Infect Ther, 2010; 8(5):505–514; doi: 10.1586/eri.10.35

18.

Giamarellou

, Kolokythas

, Petrikkos

, et al. Pharmacokinetics of three newer quinolones in pregnant and lactating women. Am J Med, 1989; 87(5A):49S–51S; doi: 10.1016/0002-9343(89)90021-1

19.

Toker

, Kızılçay

, Sagirli

. Determination of levofloxacin by HPLC with fluorescence detection in human breast milk. Bioanalysis, 2021; 13(13):1063–1070; doi: 10.4155/bio-2021-0058

20.

Wensveen

, Šestan

, Polić

. The immunology of sickness metabolism. Cell Mol Immunol, 2024; 21(9):1051–1065; doi: 10.1038/s41423-024-01192-4

21.

Bahadoran

, Bezavada

, Smallwood

. Fueling influenza and the immune response: Implications for metabolic reprogramming during influenza infection and immunometabolism. Immunol Rev, 2020; 295(1):140–166; doi: 10.1111/imr.12851

22.

Kim

, Jung

, Shin

, et al. Induction of interleukin-1 beta (IL-1β) is a critical component of lung inflammation during influenza a (H1N1) virus infection: Induction of interleukin-1 beta during influenza virus infection. J Med Virol, 2015; 87(7):1104–1112; doi: 10.1002/jmv.24138

23.

Kohn

, Dinavitser

, Berlin

, et al. Magnitude of lamotrigine exposure through breastfeeding. Breastfeed Med, 2022; 17(4):341–348; doi: 10.1089/bfm.2021.0304

24.

Anderson

, Sauberan

. Modeling drug passage into human milk. Clin Pharmacol Ther, 2016; 100(1):42–52; doi: 10.1002/cpt.377

25.

Verstegen

RHJ

, Anderson

, Ito

. Infant drug exposure via breast milk. Br J Clin Pharmacol, 2022; 88(10):4311–4327; doi: 10.1111/bcp.14538

26.

Cahill

, Bailey

, Chien

, et al. Levofloxacin secretion in breast milk: A case report. Pharmacotherapy, 2005; 25(1):116–118; doi: 10.1592/phco.25.1.116.55616

27.

Akorn. Levofloxacin injection prescribing information. 2018. Available from: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=4438fed2-7ef5-488f-baa8-39bc65768d1d [Last accessed: May 8, 2025].

28.

Wang

, Li

, Han

, et al. iE-DAP induced inflammatory response and tight junction disruption in bovine mammary epithelial cells via NOD1-dependent NF-κB and MLCK signaling pathway. Int J Mol Sci, 2023; 24(7):6263; doi: 10.3390/ijms24076263

29.

, Chen

, Huang

, et al. Safety of quinolones in children: A systematic review and meta-analysis. Paediatr Drugs, 2022; 24(5):447–464; doi: 10.1007/s40272-022-00513-2

30.

Sun

, Huang

, Zhou

, et al. Antibiotic exposure and risk of overweight/obesity in children: A biomonitoring-based study from eastern jiangsu, China. Front Public Health, 2024; 12:1494511; doi: 10.3389/fpubh.2024.1494511

31.

Han

, Teng

, Han

, et al. Antibiotic-associated changes in Akkermansia muciniphila alter its effects on host metabolic health. Microbiome, 2025; 13(1):48; doi: 10.1186/s40168-024-02023-4

32.

Szajewska

, Scott

, de Meij

, et al. Antibiotic-perturbed microbiota and the role of probiotics. Nat Rev Gastroenterol Hepatol, 2025; 22(3):155–172. Available from: https://www-nature-com-s.web.bisu.edu.cn/articles/s41575-024-01023-x [cited 2025 Feb 27].

33.

Lebeaux

, Madan

, Nguyen

, et al. Impact of antibiotics on off-target infant gut microbiota and resistance genes in cohort studies. Pediatr Res, 2022; 92(6):1757–1766; doi: 10.1038/s41390-022-02104-w

34.

Taiorazova

, Alimbayeva

, Tanatarov

, et al. A modern look at the development of intrauterine pneumonia in premature newborns: Literature review. Respir Physiol Neurobiol, 2023; 314:104073; doi: 10.1016/j.resp.2023.104073

35.

, Guo

, Wang

, et al.; Chinese Neonatal Network. Association of neonatal outcome with birth weight for gestational age in Chinese very preterm infants: A retrospective cohort study. Ital J Pediatr, 2024; 50(1):203; doi: 10.1186/s13052-024-01747-1