Inappropriate Antimicrobial Regimen Leading to Recurrent Listeria monocytogenes Meningitis: A PK/PD-Based Case Analysis and a Literature Review

Abstract

Objective

To elucidate the pharmacokinetic/pharmacodynamic (PK/PD) characteristics of antimicrobial agents used in the treatment of Listeria monocytogenes (L. monocytogenes) meningitis and to provide evidence-based guidance for individualized dosing regimens in clinical practice.

Methods

A combined approach involving retrospective case analysis and a literature review was employed. The PK/PD characteristics of various antimicrobial agents applicable to the treatment of L. monocytogenes meningitis were comprehensively evaluated, and the rationality of different dosing regimens was assessed.

Results

Case analysis revealed that inappropriate antimicrobial selection and insufficient dosing contributed to early disease relapse during treatment. Furthermore, a review of 43 published case reports has demonstrated that ampicillin in combination with gentamicin remains the first-line therapy for L. monocytogenes meningitis. However, when penicillin-based agents are contraindicated, alternative antimicrobial agents should be selected according to cerebrospinal fluid (CSF) penetration and PK/PD characteristics, with optimized and standardized dosing regimens established accordingly.

Conclusion

Selection of antimicrobial therapy for L. monocytogenes meningitis should be guided by pharmacokinetic principles. Individualized precision therapy based on lesion-site PK/PD characteristics is essential to improve treatment success and patient prognosis.

Introduction

Listeria monocytogenes (L. monocytogenes) is a facultative intracellular gram-positive bacillus and the principal species responsible for human listeriosis. It is also the only Listeria species known to cause central nervous system (CNS) infections in humans.¹ L. monocytogenes is a highly resilient pathogen that can survive in soil, water, fish, meat, vegetables, and dairy products. Notably, it is capable of continued growth and proliferation at 4°C, making it one of the major foodborne pathogens threatening the safety of refrigerated foods.^2,3 Elderly individuals, neonates, pregnant women, and immunocompromised patients are particularly susceptible to L. monocytogenes infection.^3–5 Diseases caused by L. monocytogenes are collectively referred to as listeriosis. In North America and Europe, listeriosis is among the leading causes of hospitalization due to foodborne infections. In 2010 alone, Listeria infection was estimated to cause 23,150 cases and 5463 deaths worldwide, accounting for approximately 172,823 disability-adjusted life years (DALYs).⁶ The incidence of human listeriosis varies geographically, ranging from approximately 0.1 to 11.3 cases per million population annually.⁷ Although relatively uncommon, listeriosis is associated with substantial mortality.⁸ Between 2010 and 2019, the case fatality rate of non-pregnancy-associated listeriosis in Germany was approximately 13%,⁹ lower than the reported mortality rates in Europe (15.6%) and the United States (21%).^10,11 In France, however, the 3-month mortality rate of Listeria-associated bacteremia reached 45%, while CNS infections caused by L. monocytogenes were associated with a mortality rate of approximately 30%.⁴

Ampicillin is recommended as the first-line antimicrobial agent for the treatment of listeriosis. However, the unavailability of ampicillin in certain hospitals, penicillin allergies, or other clinical conditions requiring avoidance of β-lactam antibiotics may preclude the use of standard first-line regimens. Under such circumstances, the selection and optimization of appropriate antimicrobial dosing strategies are critical determinants of therapeutic efficacy and patient prognosis. In immunocompetent individuals, L. monocytogenes infections typically manifest as mild febrile gastroenteritis. In contrast, immunocompromised or immunosuppressed patients are at a substantially higher risk of developing severe invasive diseases, including septicemia and meningitis.^1,12,13 L. monocytogenes commonly reaches the CNS via hematogenous dissemination, subsequently leading to meningitis.¹⁴ However, as a foodborne pathogen, L. monocytogenes must traverse at least two critical host barriers (the intestinal barrier and the blood-brain barrier [BBB]) before invading the CNS and causing neurological disease.^3,15 Although the BBB protects the brain against microbial invasion, it substantially limits the penetration of therapeutic agents, posing a major challenge in the treatment of bacterial meningitis. L. monocytogenes generally exhibits low rates of antimicrobial resistance; however, in cases of L. monocytogenes meningitis, cerebrospinal fluid (CSF) penetration of antimicrobial agents must be carefully considered. Previous studies have suggested that to achieve effective antibacterial activity during the early stage of treatment, the CSF penetration rate of antimicrobial agents should ideally reach 20–30%.¹⁶ Therefore, a thorough understanding of the pharmacokinetic/pharmacodynamic (PK/PD) characteristics of antimicrobial agents used for L. monocytogenes infection is essential to select the most appropriate agents with favorable BBB permeability, enabling prompt and effective antimicrobial therapy while minimizing patient risk.

Patients with Systemic Lupus Erythematosus (SLE) are at a substantially increased risk of severe bacterial infections due to underlying immune dysfunction.¹⁷ A recent Canadian study demonstrated that compared with non-SLE patients, individuals with SLE exhibited an 82% increase in the incidence of severe infections and a 61% increase in infection-related mortality.¹⁸ Penicillin acts as a hapten that binds to endogenous proteins to form complete antigens, thereby activating the immune system and potentially triggering or exacerbating SLE activity.¹⁹ Although adverse effects of penicillin on SLE do not occur universally, in routine clinical practice physicians generally avoid the use of penicillin-based antibiotics in patients with SLE to minimize potential medical risks and disputes. Consequently, penicillins are typically reserved for situations in which the anticipated benefits outweigh the risks or when no suitable therapeutic alternatives are available, and their administration is usually undertaken only after thorough physician-patient communication and informed consent. In the present study, we retrospectively analyzed the course of antimicrobial treatment in a patient with recurrent L. monocytogenes meningitis and a history of SLE. In addition, the PK/PD data regarding the recommended antimicrobial agents for L. monocytogenes infection were systematically reviewed. By comparing CSF penetration, PK/PD characteristics, and combination strategies among different anti-Listeria antimicrobial agents, we evaluated antimicrobial selection, dosing regimens, and combination therapies for L. monocytogenes meningitis from a PK/PD perspective. Furthermore, we discuss how individualized therapeutic strategies can be optimized according to pathogen-specific characteristics and host factors, with the aim of providing clinical guidance for the management of complicated cases of L. monocytogenes meningitis.

Materials and Methods

Case Presentation

A 33-year-old woman (height: 160 cm; weight: 52.5 kg; body mass index [BMI]: 20.51 kg/m²) was admitted to our hospital with “fever accompanied by fatigue and headache for more than 5 days”. Her medical history included SLE, pulmonary shadowing, and cervical disc herniation. Five days before admission, the patient developed fever without an obvious precipitating factor, with a self-measured peak temperature of 39.8°C, accompanied by fatigue and paroxysmal headache. The headache worsened during febrile episodes, with a numerical rating scale (NRS) score of 2–3. She also reported chills, rigors, occasional dizziness, nausea, myalgia, and retching, but denied cough or sputum production. Laboratory tests revealed no significant hepatic or renal dysfunction. However, the high-sensitivity C-reactive protein (hs-CRP) level was elevated at 41.98 mg/L, and the D-dimer level was 920 μg/L. At first admission (August 25-September 3, 2025), physical examination revealed a respiratory rate of 19 breaths/min, pulse rate of 105 beats/min, tympanic temperature of 38.1°C, and blood pressure of 141/105 mmHg. Neurological examination revealed neck stiffness and a positive Kernig’s sign. Therefore, purulent meningitis could not be clinically excluded. The course of antimicrobial treatment is shown in Figure 1. The initial empirical antimicrobial therapy consisted of intravenous piperacillin/tazobactam (8:1) 4.5 g twice daily. On the following day (day 2-day 3), because of the patient’s history of SLE and concerns regarding penicillin-associated lupus exacerbation, the antimicrobial regimen was changed to intravenous ceftriaxone (2 g once daily). However, the patient remained febrile despite repeated oral acetaminophen and rectal indomethacin suppositories for symptomatic fever control. Therefore, a lumbar puncture was performed for CSF analysis. On day 4 (August 28, 2025), next-generation sequencing (NGS) of CSF identified L. monocytogenes (sequence count: 38,196). Based on the microbiological findings, ceftriaxone was discontinued and antimicrobial therapy was escalated to intravenous meropenem (1 g every 8 h), together with supportive treatment. On day 6 (August 30, 2025), CSF culture yielded positive growth of L. monocytogenes. Antimicrobial susceptibility testing showed susceptibility to penicillin (minimum inhibitory concentration [MIC]: 0.5 mg/L, susceptible ≤2 mg/L) and meropenem (MIC: 0.19 mg/L, susceptible ≤0.25 mg/L). Following the initiation of meropenem therapy, the patient’s body temperature gradually normalized, hs-CRP levels improved, and headache symptoms progressively resolved. On day 10 (September 3, 2025), the patient was discharged in an improved condition and prescribed oral trimethoprim-sulfamethoxazole (TMP-SMX), 160 mg/0.8 g four times daily, as continuation antimicrobial therapy after discharge. Thirty-nine days after discharge (October 12, 2025), the patient presented to another hospital because of persistent headache. Routine CSF examination at that hospital showed a weakly positive Pandy’s reaction. The test is a qualitative phenol-based assay for globulin elevation in CSF. A positive result indicates increased CSF protein, a feature of bacterial meningitis and CNS inflammation. In light of her recent confirmed L. monocytogenes meningitis and persistent headache, this finding suggested incomplete pathogen eradication with ongoing infection. Recurrent L. monocytogenes meningitis was highly suspected, prompting reinitiation of antimicrobial therapy. She was treated with intravenous piperacillin/tazobactam (4.5 g every 8 h) combined with oral TMP-SMX (160 mg/0.8 g four times daily) for 7 days, after which the headache improved. However, five days after discharge (October 24, 2025), the headache recurred and the patient was readmitted to our hospital. Antimicrobial therapy with intravenous piperacillin/tazobactam (8:1) 4.5 g every 8 h and oral TMP-SMX (160 mg/0.8 g four times daily) was continued. During the treatment, the patient experienced recurrent fluctuations in body temperature. On day 8 (October 31, 2025), piperacillin/tazobactam was discontinued and replaced with intravenous meropenem 1 g every 8 h combined with oral TMP-SMX (160 mg/0.8 g four times daily). Thereafter, the patient’s temperature gradually stabilized, and headache symptoms improved. She was discharged on day 13 (November 5, 2025), with instructions to continue oral ampicillin capsules (1 g three times daily) purchased outside the hospital as maintenance antimicrobial therapy.

Figure 1.

Timeline of antimicrobial therapy in a patient with recurrent hospitalizations for L. monocytogenes meningitis.

Abbreviations: CSF, cerebrospinal fluid; NGS, next-generation sequencing; ivgtt, intravenously guttae; PO, oral administration; qd, once daily; bid, twice daily; tid, three times daily; qid, four times daily; q8h, every 8 hours; TMP-SMX, trimethoprim-sulfamethoxazole.

Literature Search

A literature search was conducted in the PubMed database using the following search strategy: “((listeria monocytogenes[Title/Abstract]) OR (Listeriosis[Title/Abstract])) AND (meningitis[Title/Abstract])”. Relevant studies published within the last 10 years (January 1, 2016, to December 31, 2025) concerning L. monocytogenes meningitis were retrieved. All identified articles were reviewed individually. Case reports and case series involving patients with microbiologically confirmed L. monocytogenes meningitis were included. Patients with encephalitis, rhombencephalitis, or possible mixed infections involving other bacterial pathogens were excluded. Data regarding patient sex, age, history of drug allergy, clinical manifestations, definitive antimicrobial therapy, and clinical outcomes were systematically extracted and summarized.

A total of 343 relevant publications were identified through the database retrieval. After screening according to predefined inclusion and exclusion criteria, 43 case reports and case series describing L. monocytogenes meningitis were included, comprising a total of 44 patients.^20–62 Detailed patient characteristics, including sex, age, allergy history, clinical manifestations, antimicrobial treatment after diagnosis, and prognosis, are summarized in Table 1. The age distribution of patients with L. monocytogenes meningitis is broad, ranging from neonates to elderly individuals. The most common clinical manifestations were fever (n = 36), headache (n = 20) and unconsciousness (n = 16). After a definitive diagnosis, the most frequently administered antimicrobial agents were ampicillin (n = 33) and gentamicin (n = 25). Notably, in all retrieved cases, gentamicin was administered in combination with penicillin-based antibiotics to treat L. monocytogenes meningitis. Of particular interest, only two patients with a documented penicillin allergy were identified among the included cases. Following diagnosis, the antimicrobial regimens used in these patients consisted of intravenous meropenem (2 g three times daily) and oral TMP-SMX (960 mg every 6 h).

Table 1.

Clinical Characteristics of 44 Patients with L. monocytogenes Meningitis

NO.	Sex	Age	Drug Allergy	Clinical Manifestations	Antimicrobial Regimen	Outcome
1	F	79y		Fever, headache	AMP + GM	CR
2	F	28y		Unconsciousness, agitation, neck stiffness	AMP (2 g q4h) + GM (320 mg qd)	CR
3	M	78y		Fever, unconsciousness	MEM + LZD	CR
4	F	16m		Fever, vomit, decreased appetite	AMP (200 mg/kg/d in 4 doses) + GM (5 mg/kg/d)	CR
5	F	66y		Fever, lethargy, unconsciousness	AMP/SUB (2 g/1 g q6h) + GM (120 mg qd)	De
6	M	45y		Diplopia	AMP (2 g q6h) + VAN (1 g q12h)	CR
7	M	80y		Fever, unconsciousness, headache, neck stiffness	AMP	CR
8	M	66y		Fever, headache, vomit	AMP/SUB (2 g/1 g q6h) + MEM (1 g q8h)	CR
9	F	96y		Fever, unconsciousness	AMP + TMP-SMX + MEM	CR
10	M	74y		Fever, confusion, unconsciousness	AMP (2 g q4h) + GM (80 mg q8h)	CR
11	M	72y		Weakness, dizziness, fever, urinary incontinence	AMP (2 g q6h)	CR
12	M	13y		Fever, unconsciousness	AMP (6g/d) + GM (7.5 mg/kg/d)	CR
13	F	11m		Fever, vomit, diarrhea, lethargy, uncontrolled movements of right leg	AMP (300 mg/kg/d in 3 doses) + GM (5 mg/kg/d)	CR
14	F	62y		Headache, fever	AMX	CR
15	M	74y		Vomit, diarrhea, urinary incontinence, decreased appetite, chill, headache, fever, unconsciousness, confusion	AMP + GM	CR
16	F	3y		Fever, vomit, lethargy, headache	AMP + GM	CR
17	F	20m		Fever, lethargy	AMP (400 mg/kg/d) + GM (7 mg/kg/d)	CR
18	F	/		Headache, fever, unconsciousness	MEM + PEN	CR
19	M	30y	AMX	Headache, confusion, blurred vision	MEM (2 g tid)	CR
20	F	87y		Unconsciousness, fever, decreased appetite, right upper quadrant pain	AMP (2 g q6h)	CR
21	/	15d		Fever, poor feeding, lethargy	AMP + GM	CR
22	F	64y		Fever, headache, vomit, convulsion, unconsciousness	MEM (2 g q8h) + AMP (3 g q6h)	CR
23	F	7d		Weakness, decreased appetite, fever	MEM (80 mg)	CR
24	/	11d		Fever, weakness	MEM (80 mg)	CR
25	M	64y		Chest pain, dizziness, nausea, palpitation	AMP (2 g q6h)	CR
26	M	22m		Fever, vomit, unconsciousness	MEM + AMP + GM	CR
27	F	22y		Headache, nausea, vomit	AMP (2 g q4h) + GM (80 mg q8h)	CR
28	F	90y		Fever, unconsciousness	AMP (8 g/d)	CR
29	M	37y		Headache, fever	AMX (2 g qd) + GM (80 mg tid)	CR
30	F	62y		Lethargy, confusion, fever	AMP + GM	CR
31	M	54y		Headache, vomit, chill, confusion	MEM	CR
32	M	30y	PEN	Fever, convulsion, headache, diplopia	TMP-SMX (960 mg q6h)	CR
33	M	79y		Fever, unconsciousness	AMP (2 g q4h) + GM (120 mg q8h)	CR
34	F	7y		Fever, headache, vomit, decreased appetite, photophobia	AMP + GM	CR
35	F	7m		Fever, vomit, diarrhea, strabismus	AMP (300 mg/kg/d) + GM (7.5 mg/kg/d) 5d then AMP (300 mg/kg/d) + high-dose TMP-SMX (20 mg/kg/d of TMP) 21d	CR
36	F	/		Fever, headache, vomit, chill	AMP (400 mg/kg/d in 6 doses) + GM (7.5 mg/kg/d in 3 doses)	CR
37	F	77y		Fever, unconsciousness	AMP + GM	CR
38	M	Neonate		Pale, weakness	AMP + GM	CR
39	M	7y		Unconsciousness, fever, headache, vomit, lethargy	AMP + GM (5 mg/kg/d)	CR
40	M	34y		Fever, vomit, headache	AMP (2 g q4h) + GM (3 g q8h)	CR
41	F	8y		Headache, fever, lethargy	AMP (200 mg/kg/d) + GM (6 mg/kg/d)	CR
42	F	28y		Fever, headache, photophobia, myalgias	AMX + GM (3 mg/kg/d)	CR
43	M	3y		Fever, multiple generalized tonic-clonic seizures	AMX + AMK	CR
44	M	62y		Headache, neck stiffness, confusion	VAN + AMP	CR

Abbreviations: M, male; F, female; y, -year-old; m, -month-old; d, days; CR, clinical recovery; De, death; AMP, ampicillin; GM, gentamicin; MEM, meropenem; LZD, linezolid; SUB, sulbactam; VAN, vancomycin; TMP-SMX, trimethoprim-sulfamethoxazole; AMX, amoxicillin; PEN, penicillin; AMK, amikacin; qd, once daily; tid, three times daily; q4h, every 4 hours; q6h, every 6 hours; q8h, every 8 hours; q12h, every 12 hours.

Discussion

Antimicrobial Susceptibility Characteristics of L. monocytogenes and Changes in Antimicrobial Resistance Over Time

The antimicrobial susceptibility profile of a pathogen provides a critical basis for selecting targeted antimicrobial therapies. In the cases of L. monocytogenes meningitis summarized in the present review, ampicillin, gentamicin, and meropenem were the most frequently administered agents, reflecting the extensive clinical experience supporting their efficacy against this pathogen. In fact, L. monocytogenes has a highly closed genome, limited population interactions, and a small population size, which may contribute to the currently relatively low rates of antimicrobial resistance.⁶³ A study conducted in Mexico investigated the susceptibility of food-derived L. monocytogenes isolates to 12 antimicrobial agents according to the standards of the Clinical and Laboratory Standards Institute (CLSI) and the European Committee on Antimicrobial Susceptibility Testing (EUCAST).⁶⁴ Using the Kirby-Bauer disk diffusion method, that study found all isolates to be susceptible to ampicillin, chloramphenicol, gentamicin, levofloxacin, penicillin, tetracycline, and vancomycin. Meanwhile, an analysis of clinical L. monocytogenes isolates from Hebei Province, China, reported resistance rates of 2.2% for penicillin, 1.4% for ampicillin, 2.0% for meropenem, 3.7% for erythromycin, and 1.6% for TMP-SMX.⁶⁵ However, it should be noted that the widespread use of antimicrobial agents and associated environmental changes may facilitate the acquisition of resistance by L. monocytogenes. Indeed, a 2022 study demonstrated that the non-susceptibility rates of L. monocytogenes isolates to first-line drugs (ampicillin, amoxicillin, penicillin, gentamicin, and TMP-SMX) were significantly higher during the recent period (2014–2021) than in earlier periods (2000–2006 and 2007–2013).⁶⁶ Although resistance rates reported across different studies vary considerably, which may be attributable to differences in geographic region, strain origin, and bacterial genotype,^67–70 a clear trend toward increasing resistance over time remains apparent.

In the present case, CSF culture confirmed L. monocytogenes that was susceptible to both penicillin and meropenem. Given the patient’s history of SLE and concerns about penicillin-induced exacerbation of SLE activity, meropenem was selected as the primary antimicrobial agent. This therapeutic decision was consistent with both the patient’s individualized clinical characteristics and the pathogen’s susceptibility pattern. Nevertheless, antimicrobial efficacy is ultimately determined by drug exposure at the infection site. Owing to the unique nature of intracranial infections, a detailed understanding of the PK/PD characteristics of antimicrobial agents active against L. monocytogenes is essential for precise antimicrobial therapy.

PK/PD-Based Analysis of the Therapeutic Regimen in the Present Case

Antimicrobial susceptibility profiles merely reflect in vitro activity. Owing to the barrier properties of the BBB, the therapeutic efficacy of antimicrobial agents against L. monocytogenes meningitis largely depends on whether adequate drug concentrations exceeding the MIC can be achieved within the CNS. Among pharmacokinetic parameters, the CSF-to-serum area under the concentration-time curve ratio (AUC_CSF/AUC_S) is considered a key indicator for evaluating BBB penetration capacity. As shown in Figure 2, piperacillin has been reported to exhibit a poor BBB penetration capacity under normal or mildly inflamed meningeal conditions (AUC_CSF/AUC_S = 0.034), whereas this penetration capacity rises markedly in cases of severe meningitis (AUC_CSF/AUC_S = 0.32).⁷¹ Nevertheless, for piperacillin/tazobactam, the initial empirical regimen used in this patient, the clinical efficacy appeared to be unsatisfactory. One possible explanation is that the administered dosage was insufficient to achieve intracranial drug concentrations that exceeded the MIC of the susceptible pathogen. Previous studies have suggested that piperacillin may not be suitable for most CNS infections and is not recommended for L. monocytogenes meningitis. Therefore, even with a higher dosage regimen than that originally used in this patient, piperacillin is unlikely to eradicate CNS pathogens with MIC values exceeding 0.5 μg/mL, including L. monocytogenes, Staphylococcus aureus, Escherichia coli, Staphylococcus epidermidis, and Pseudomonas aeruginosa.⁷² Therefore, although antimicrobial susceptibility testing in the present patient demonstrated a penicillin MIC of 0.5 μg/mL, inadequate dosing may have resulted in insufficient intracranial drug exposure, ultimately leading to poor therapeutic efficacy. In subsequent treatment, after the diagnosis of L. monocytogenes meningitis was established, penicillin-class antibiotics were avoided because of the patient’s history of SLE. Based on the CSF antimicrobial susceptibility results, 1 g of intravenous meropenem administered every 8 h was selected as the primary antimicrobial regimen. Of note, as shown in Figure 2, meropenem has been demonstrated to achieve favorable BBB penetration in the setting of severe meningitis (AUC_CSF/AUC_S = 0.39).⁷¹ Thus, while the choice of the antibacterial agent was clinically reasonable, the dosing regimen remains a matter of further consideration. For patients with normal renal function, the prescribing information for meropenem recommends a dosage of 2 g every 8 h for meningitis treatment. In patients with L. monocytogenes meningitis or bacteremia, the therapeutic efficacy of meropenem is highly dependent on dosing intensity, and failure to achieve meningitis-recommended dosing regimens may result in treatment failure or disease recurrence.⁷³ Therefore, administration of meropenem at 2 g every 8 h is likely to be more appropriate in this patient. Furthermore, TMP-SMX was used in combination with other antimicrobial agents during the subsequent two hospitalizations, serving as an additional agent for the treatment of listerial infection. TMP-SMX has been shown to exhibit favorable BBB penetration, as illustrated in Figure 2. In high-dose regimens, CSF drug concentrations can exceed the MIC of susceptible pathogens, supporting its use in the treatment of L. monocytogenes meningitis.⁷¹ Trimethoprim and sulfamethoxazole alone exhibit moderate antibacterial activity against L. monocytogenes, but their combined use produces enhanced bactericidal effects.^74,75 Therefore, adding TMP-SMX to piperacillin/tazobactam or meropenem for the treatment of L. monocytogenes meningitis may enhance therapeutic efficacy and compensate for the shortcomings of monotherapy. However, it should be noted that TMP-SMX has been reported to carry a risk of aseptic meningitis,⁷⁶ which may further complicate the clinical management of L. monocytogenes meningitis. Consequently, TMP-SMX is currently regarded as a second-line therapeutic option for the treatment of L. monocytogenes meningitis.⁷⁷

Figure 2.

AUC_CSF/AUC_S and PK/PD indices of antimicrobial agents used for the treatment of L. monocytogenes meningitis. Boldface type indicates estimates for AUC_CSF/AUC_S of the antibiotic classes based on available data.

PK/PD Landscapes of Antimicrobials for L. monocytogenes Meningitis

To better guide antimicrobial therapy for L. monocytogenes meningitis, we reviewed the literature on commonly used regimens for this infection, as well as agents with extensive clinical experience in CNS infections, and summarized the AUC_CSF/AUC_S ratios and PK/PD characteristics of several recommended agents (Figure 2).

Ampicillin is widely recognized as the first-line agent for the treatment of L. monocytogenes meningitis, and its CSF concentration exceeds that of amoxicillin.⁷⁸ The CSF/serum concentration ratio of ampicillin is influenced by the extent of meningeal inflammation, with values reaching 13–14% in the presence of an inflammatory response.⁷⁹ Penicillin-class antibiotics, including ampicillin, exhibit time-dependent antibacterial activity, and their therapeutic efficacy primarily depends on the duration for which drug concentrations at the infection site remain above the minimum inhibitory concentration (T > MIC). Although penetration of penicillin into the CSF is relatively limited in patients with mild meningitis, resulting in comparatively reduced efficacy, these agents retain potent antibacterial activity against susceptible pathogens. Previous studies have demonstrated that even at concentrations below the MIC, penicillin can reduce the production of LLO, an essential virulence factor of L. monocytogenes.⁸⁰ However, at sufficiently high concentrations, penicillins can completely eradicate the pathogen.⁸¹ Under standard dosing regimens, the CSF concentrations of penicillins in patients with meningitis can approach the MIC of intermediately susceptible pathogens. In cases of severe L. monocytogenes meningitis, the estimated AUC_CSF/AUC_S ratio of penicillins may further increase to approximately 0.2, thereby enhancing antibacterial efficacy.⁷¹ In addition, penicillin is generally associated with relatively low toxicity. Therefore, when treating intracranial infections caused by moderately susceptible pathogens, the daily dose of certain penicillin agents may be appropriately increased without causing severe adverse reactions.⁷⁹ As a result, penicillin-class antimicrobial agents are generally recommended as the first-line therapeutic option for L. monocytogenes meningitis.

Aminoglycosides exhibit concentration-dependent antibacterial activity, and their therapeutic efficacy is primarily associated with the 24 h area under the concentration-time curve-to-minimum inhibitory concentration ratio (24 h AUC/MIC). Higher drug concentrations relative to the pathogen MIC were associated with greater rates and extents of bacterial killing. Aminoglycosides are frequently administered in combination with penicillin-class antibiotics to treat listeriosis. In vitro studies have demonstrated synergistic activity between aminoglycosides and penicillin/ampicillin against L. monocytogenes.^82–84 Moreover, two large cohort studies have reported improved clinical outcomes in patients with Listeria infections treated with β-lactam antibiotics combined with aminoglycosides.^4,85,86 Although definitive evidence supporting the clinical benefit of this combination therapy remains limited,⁷⁴ the estimated CSF penetration ratio of aminoglycosides under normal physiological conditions or mild meningitis (AUC_CSF/AUC_S = 0.2) suggests that CSF concentrations may still reach the MIC of intermediately susceptible pathogens during meningitis.⁷¹ Therefore, aminoglycosides are commonly used together with ampicillin as first-line therapy for L. monocytogenes meningitis.

Fluoroquinolones, including levofloxacin and moxifloxacin, also exhibit antibacterial activity against L. monocytogenes. Based on their AUC_CSF/AUC_S, fluoroquinolones demonstrate substantially greater penetration into the CSF than β-lactam antibiotics under non-meningitic conditions (levofloxacin, 0.71; moxifloxacin, 0.46), allowing CSF drug concentrations to exceed the MIC of susceptible pathogens.⁷¹ However, fluoroquinolones exhibit concentration-dependent antibacterial activity, and their therapeutic efficacy is closely associated with the 24 h AUC/MIC ratio. Consequently, antibacterial activity depends heavily on dosing intensity. Pea et al reported that intravenous levofloxacin administered at 0.5 g every 12 h exhibited efficient penetration across the BBB into the CSF; however, CSF drug concentrations remained insufficient to eradicate pathogens with MIC values >0.5 mg/L, suggesting that higher dosing regimens may be required.⁸⁷ Nevertheless, the clinical application of fluoroquinolones in CNS infections is limited by their potential neurotoxicity, including encephalopathy, seizures, and peripheral neuropathy.^88–91 Thus, fluoroquinolones are considered only as second-line therapeutic alternatives for the treatment of L. monocytogenes meningitis.

Carbapenems and penicillins both belong to the β-lactam class of antimicrobial agents and, therefore, share similar PK/PD characteristics, including time-dependent antibacterial activity (T > MIC). However, carbapenems generally exhibit superior CSF penetration compared with penicillins, with the estimated AUC_CSF/AUC_S reaching approximately 0.3 in severe meningitis.⁷¹ Among carbapenems with extensive clinical experience in treating CNS infections, meropenem is the most widely used. Under normal meningeal conditions, the reported AUC_CSF/AUC_S of meropenem ranges from 0.047 to 0.25. However, this value may increase to approximately 0.39 in the presence of meningitis. Consequently, CSF meropenem concentrations in patients with meningitis can approach the MIC of intermediately susceptible pathogens and achieve therapeutic levels.^71,92 Although imipenem can also attain therapeutic concentrations in the CSF, it is associated with a higher risk of adverse CNS effects, particularly seizures. One study reported a seizure incidence of up to 33% among pediatric patients with bacterial meningitis treated with intravenous imipenem.⁹³ Therefore, meropenem is generally preferred over imipenem for the treatment of L. monocytogenes meningitis. However, owing to safety and economic considerations, meropenem is recommended only as an alternative to ampicillin when the latter is not available.

Linezolid is an oxazolidinone antibiotic that is considered an alternative therapeutic option for ventriculitis and meningitis caused by multidrug-resistant gram-positive pathogens, including methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococci (VRE). Linezolid exhibits concentration-dependent antibacterial activity, with efficacy primarily associated with the 24 h AUC/MIC ratio, and demonstrates excellent penetration into the CSF. Even in the absence of meningitis, its estimated AUC_CSF/AUC_S can reach approximately 0.8–1, allowing CSF drug concentrations to substantially exceed the MIC of susceptible pathogens, even under standard dosing regimens.⁷¹ Linezolid has demonstrated efficacy in the treatment of CNS infections caused by multidrug-resistant organisms and has also been reported as a feasible therapeutic option for CNS infections caused by L. monocytogenes.^25,94 Moreover, accumulating evidence suggests that combination therapy with linezolid and meropenem may represent a more effective treatment strategy.^95,96 However, despite these promising findings, linezolid is generally considered only as an alternative therapeutic option for L. monocytogenes meningitis. This may be attributable to its potential for serious adverse effects, including myelosuppression, peripheral neuropathy, and thrombocytopenia.

Conclusion

L. monocytogenes meningitis carries high mortality, and timely and effective antimicrobial therapy is critical. Through a literature review and comparative analysis of a case with recurrent hospitalizations due to treatment failure, we emphasize that clinical decision-making in L. monocytogenes meningitis should not rely solely on in vitro antimicrobial susceptibility results. Instead, antimicrobial susceptibility data must be integrated with CSF drug exposure data to guide therapy. However, empirical treatment alone is insufficient for optimal disease management. Individualized therapeutic strategies guided by pharmacokinetic principles should be established, with comprehensive consideration of drug penetration, patient pathophysiological status, and combination regimens. Precision antimicrobial therapy based on lesion-site PK/PD characteristics is essential for improving treatment success rates and optimizing patient outcomes.

Funding Statement

This study did not receive any specific grants from funding agencies in the public, commercial, or nonprofit sectors.

Data Sharing Statement

The original contributions of this study are included in this article. Further inquiries can be directed to the corresponding authors.

Ethics Approval

This study was conducted in accordance with the principles of the Declaration of Helsinki. The Institutional Review Board (IRB) of Shaoxing People’s Hospital reviewed the study and determined that it was exempt from ethical approval owing to its retrospective design. All patient data were anonymized prior to analysis. Written informed consent was obtained from the patient for publication of this case report and any accompanying images.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis, and interpretation, or in all these areas, took part in drafting, revising, or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Disclosure

The authors have no conflicts of interest to declare.