In an immunocompromised patient with EBV DNA in cerebrospinal fluid, three necrotic‑core ring‑enhancing brain lesions, and stopped empiric anti‑toxoplasma therapy, what is the significance of a positive Klebsiella pneumoniae carbapenemase (KPC) PCR on the brain biopsy and how should it be managed?

KPC PCR on Brain Biopsy: Significance and Management

A positive KPC PCR on brain biopsy in this immunocompromised patient with EBV DNA in CSF and ring-enhancing lesions most likely represents contamination or colonization rather than true CNS infection, and the primary diagnosis remains HIV-associated primary CNS lymphoma requiring immediate initiation of rituximab plus high-dose methotrexate alongside optimized antiretroviral therapy. 1

Critical Diagnostic Context

Why KPC is Unlikely the Primary Pathogen

• EBV DNA detection in CSF is positive in >96% of HIV-associated primary CNS lymphoma cases and is the single most important diagnostic test for this condition 1
• The combination of profound immunosuppression, EBV-positive CSF, and multiple ring-enhancing lesions with necrotic cores is the classic presentation of HIV-associated PCNSL, not bacterial brain abscess 1
• KPC-producing Klebsiella pneumoniae causes systemic infections (bloodstream, respiratory, urinary tract) but is not a recognized cause of primary CNS infection or encephalitis 2, 3, 4
• Brain biopsy specimens can be contaminated during the procedure or processing, and PCR detection of bacterial DNA does not establish active infection 5

Understanding KPC PCR Detection

• KPC PCR is designed to detect the blaKPC gene (encoding carbapenemase enzymes), not to diagnose active infection 6, 5
• Real-time PCR for KPC genes is highly sensitive and can detect even small amounts of bacterial DNA, including from non-viable organisms or environmental contamination 5
• The test was developed for surveillance and rapid identification of carbapenem resistance in clinical isolates, not for direct tissue diagnosis 5
• A positive PCR without corresponding culture growth, clinical signs of bacterial infection, or appropriate CSF findings (neutrophilic pleocytosis, hypoglycorrhachia, elevated protein) suggests the DNA detected is not from an active pathogen 2

Recommended Management Approach

Immediate Actions

Prioritize treatment of HIV-associated PCNSL over empiric antibacterial therapy:

• Initiate rituximab combined with high-dose methotrexate (3 g/m²) immediately, which yields median overall survival of 5.7 years and 5-year survival of 48-67% 1
• Start or optimize fully active antiretroviral therapy (ART) concurrently—this is mandatory and directly improves long-term disease control 1
• Provide Pneumocystis jirovecii prophylaxis (trimethoprim-sulfamethoxazole) given the patient's immunocompromised state 2, 1

Addressing the KPC Finding

Do not initiate empiric anti-KPC antibiotics unless there is clear evidence of bacterial infection:

• Review the brain biopsy histopathology for evidence of bacterial abscess (neutrophilic infiltration, gram-positive organisms on special stains) versus lymphoma (atypical lymphoid infiltrate, EBV positivity by immunohistochemistry) 1
• Send brain biopsy tissue for bacterial culture—culture remains the gold standard for diagnosing bacterial infection 2
• Assess for systemic signs of KPC infection: obtain blood cultures, check for pneumonia on chest imaging, evaluate for urinary tract infection 2, 4
• Review CSF parameters: bacterial CNS infection typically shows neutrophilic pleocytosis (>100 WBCs/mm³), glucose <40 mg/dL, and protein >100 mg/dL 2

If True KPC CNS Infection is Confirmed

Only if culture grows KPC-producing organisms or overwhelming clinical/histopathologic evidence supports bacterial brain abscess:

• Novel β-lactam agents such as ceftazidime/avibactam or meropenem/vaborbactam should be first-line treatment for KPC-producing infections 2
• Imipenem/relebactam and cefiderocol are alternative options 2
• Traditional antibiotics (colistin-based regimens) have poor efficacy with approximately one in three patients dying 2
• Consult infectious disease specialists for guidance on dosing and duration, as CNS penetration data for newer agents is limited 2

Critical Pitfalls to Avoid

• Do not delay lymphoma-directed therapy based solely on a positive PCR without confirmatory culture or histopathologic evidence of bacterial infection 1
• Avoid empirical treatment for toxoplasmosis when CSF EBV DNA is positive and imaging is characteristic for lymphoma—this patient already appropriately stopped anti-toxoplasma therapy 1
• Do not use whole-brain radiotherapy as first-line treatment; reserve it for chemorefractory disease or palliative intent 1
• Never delay ART initiation—concurrent ART is mandatory and measurably impacts survival in HIV-associated PCNSL 1
• Recognize that corticosteroids should be avoided before definitive tissue diagnosis as they obscure histopathology 1

Additional Diagnostic Considerations

• Obtain whole-body FDG-PET/CT to exclude systemic lymphoma, which would reclassify the disease as secondary CNS lymphoma 1
• Perform ophthalmologic examination as ocular lymphoma occurs in 5-20% of HIV-PCNSL patients 1
• Measure serum lactate dehydrogenase (LDH) as an additional tumor marker 1
• Consider testicular ultrasound in male patients to rule out occult systemic disease (present in ~8% of cases) 1