Abstract
Neurosyphilis remains a severe manifestation of syphilis, particularly in individuals living with HIV, where atypical presentations and treatment challenges are more common. Although ceftriaxone is considered an alternative to penicillin G, emerging reports suggest possible therapeutic failure in immunocompromised hosts. We describe a 63-year-old man with well-controlled HIV infection who developed seizures and altered mental status. Cerebrospinal fluid analysis confirmed neurosyphilis, and he was treated with high-dose intravenous ceftriaxone (2 g twice daily) for ten days. Despite therapy, neurological symptoms persisted, and repeat investigations showed ongoing inflammation. Ceftriaxone was replaced with intravenous doxycycline (100 mg twice daily), resulting in rapid clinical improvement within 72 hours. Follow-up cerebrospinal fluid studies and imaging demonstrated complete resolution of inflammatory changes. The patient completed a 28-day doxycycline course with sustained recovery. This case underscores the potential for ceftriaxone failure in HIV-associated neurosyphilis and supports considering doxycycline as an effective alternative in refractory cases.
Introduction
Neurosyphilis is a known complication of syphilis that can occur at any stage of infection and is particularly concerning in people with HIV (PWH). 1 Ceftriaxone is widely accepted as an alternative to penicillin G for neurosyphilis, especially in patients with penicillin allergy or limited access. 2 However, clinical response may be diminished in immunocompromised hosts, and therapeutic failure with ceftriaxone, although uncommon, has been reported.3,4
Case description
A 63-year-old man with HIV, diagnosed 10 years ago, presented with new-onset generalized tonic-clonic seizures and confusion. He was on Tablet Efavirenz 600 mg, Capsule Emtricitabine 200 mg, and Tablet Tenofovir Alafenamide 25 mg, all once daily, and HIV was well under control. On arrival CD4% 31.39%, Absolute CD4 count 209 cells/mcl, HIV viral load copies <50/ml. He had past history of documented TPHA positive (1:512) 6 years back but was not treated for the same. As the patient’s GCS was less than seven, he was electively intubated for airway protection. Antiepileptic medicines were titrated in view of seizures and EEG. MRI of the brain showed diffuse leptomeningeal enhancement (Figure 1). CSF analysis revealed 400 cells/mm3 (60% neutrophils), protein 134.8 mg/dL, glucose 132 mg/dL (serum glucose: 300 mg/dL), and reactive TPHA and RPR, serum RPR titer was 1:2 and CSF titer of RPR was 1:4. As penicillin was very difficult to procure, he was started on intravenous ceftriaxone (2 g twice daily) for neurosyphilis. Patient GCS was remaining around 3/10 and maintaining hemodynamic parameters. Along with CSF culture, blood and urine culture were also sent, which revealed no growth. CSF Genexpert, biofire, galactomannan, beta-D- glucan, routine culture, cytology and tuberculosis XDR pyrosequensing was negative. Despite 10 days of therapy, his neurological status (GCS E1VTM1) remained unchanged. A second CSF analysis showed persistent pleocytosis (180 cells/mm3, 96% lymphocytes), protein 87.4 mg/dL, and TPHA positivity. Repeat MRI confirmed persistent meningeal enhancement (Figure 2). Doxycycline (100 mg IV twice daily) was added and ceftriaxone was stopped. Within 72 hours, GCS improved to E4M6Vt. The patient Gradually stabilized, was weaned off the ventilator, shifted to the step down ICU, and latter to the ward. The patient’s GCS improved, and he was decannulated from the tracheostomy. Aggressive neuro-rehabilitation was continued. Follow-up CSF (Day 21) revealed improved values (Table 1), and MRI showed resolving inflammation (Figure 3). The patient received total 28 days of doxycycline. The patient was discharged ambulatory and neurologically stable. MRI brain with contrast suggestive of leptomeningeal enhancement. MRI brain with contrast suggestive of nearly same leptomeningeal enhancement as previous scan. Serial CSF parameters. MRI brain with contrast suggestive of resolution of leptomeningeal enhancement as compared to previous 2 scans. 
Discussion
Neurosyphilis in individuals living with HIV often presents with atypical clinical features and may demonstrate a varied response to treatment due to the host’s immunocompromised status. This variation in presentation and treatment response underscores the need for a tailored therapeutic approach. Although ceftriaxone has gained widespread acceptance as an alternative to penicillin G—particularly in cases where penicillin is either contraindicated or difficult to access—its efficacy in the central nervous system (CNS), particularly among immunosuppressed patients, remains inadequately defined.2,5 While ceftriaxone has known CSF penetration, factors such as host immunity, CNS inflammation, and bacterial load may affect its pharmacodynamics in individuals living with HIV.4,6
In the case presented, the patient’s lack of neurological improvement despite receiving 10 days of high-dose intravenous ceftriaxone points toward probable therapeutic failure. This assumption is supported by persistently abnormal CSF findings—especially the continued pleocytosis and elevated protein—and radiological evidence of ongoing meningeal inflammation. Importantly, the patient’s neurological condition showed remarkable and rapid improvement following initiation of doxycycline, which led to both clinical stabilization and radiological resolution.
While doxycycline is not typically considered a first-line therapy for neurosyphilis, accumulating evidence suggests that it possesses treponemicidal properties and is capable of achieving adequate CSF concentrations, especially in the presence of meningeal inflammation.6,7 These properties support its use in selected cases where first-line therapies fail or are inaccessible. In this context, our patient’s response to doxycycline strengthens the case for its potential role as a viable alternative therapy, particularly in individuals living with HIV who exhibit poor responses to ceftriaxone.
Furthermore, several studies have indicated that individuals with low CD4 counts, elevated CSF protein levels, or advanced HIV disease are at a higher risk of treatment failure when treated with standard therapies such as ceftriaxone.3,8,9 These findings align with our patient’s profile and suggest that close clinical and laboratory monitoring is essential to promptly identify non-responders and escalate or switch treatment accordingly. 10
This case serves to emphasize the importance of maintaining a high index of suspicion for therapeutic failure, even when a guideline-endorsed treatment regimen is being administered.1,2 It also highlights the necessity of individualized therapy and reconsideration of alternative treatment options, such as doxycycline, in select scenarios of neurosyphilis among people with HIV.
Conclusion
In HIV-associated neurosyphilis, clinical non-response to ceftriaxone may warrant early consideration of doxycycline.
Footnotes
Consent to participate
Written informed consent was obtained from the patient for publication of this case and accompanying images.
Author contributions
All authors contributed to patient care, data collection, and manuscript preparation. All authors reviewed and approved the final manuscript.
Funding
The authors received no financial support for the research, authorship, and/or publication of this article.
Declaration of conflicting interests
The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.