Brian Ubhaus, PharmD, is a PGY-1 pharmacy practice resident at St Joseph’s University Medical Center in Paterson, NJ. He completed his PharmD at the Ernest Mario School of Pharmacy at Rutgers University in Piscataway, NJ.

Brian Ubhaus, PharmD

A 52-year-old man initially presented to the hospital with a diagnosis of cerebellar tumor without associated hydrocephalus. One month later he returned to the hospital with worsening neurologic symptoms and was found to have hydrocephalus. At this time he underwent extraventricular drain (EVD) placement; however, the hydrocephalus continued to worsen, prompting removal of the EVD and placement of a ventriculoperitoneal (VP) shunt. Nine days after placement, he returned to the hospital once again with a chief complaint of severe headache that had worsened over the 3 hours prior to admission with no alleviating or exacerbating factors. He also reported abdominal pain underlying the incision site from the VP shunt placement. He denied fever, chills, nausea, vomiting, and diarrhea.

The patient’s medical history included type 2 diabetes mellitus, hypertension, and cerebellar tumor. His surgical history included a craniotomy for cerebellar tumor, followed by a ventriculostomy and EVD placement the month prior to admission, as well as the VP shunt placement 9 days prior to admission.

Before admission, the patient was taking aspirin 81 mg, atorvastatin 80 mg, lisinopril 5 mg, pantoprazole 40 mg, and dexamethasone 2 mg, all daily.

The patient resided at a subacute rehabilitation facility. He had previously worked for an engineering firm but denied any chemical or toxin exposure. He also denied the use of tobacco, illicit drugs, and alcohol, and his family history was noncontributory.

Upon presenting to the hospital, the patient was awake and alert but in moderate pain. He was tachycardic, with a heart rate of 110 beats per minute, but all other vital signs were within normal limits. Staples were in place on the left side lateral occipital and posterior occipital sites from the VP shunt placement. His physical exam was remarkable for mild neck stiffness and diffuse abdominal tenderness, which was worse at the incision site where the shunt had been placed. His neurologic exam was normal.

Initial labs were significant for leukocytosis with a white blood cell (WBC) count of 18.1 cells/mm3 (4.5-11.0 cells/mm3). The remainder of the complete blood count and basic metabolic panel was unremarkable. Inflammatory markers were elevated, with a C-reactive protein level of 11.70mg/dL (<0.99 mg/dL) and an erythrocyte sedimentation rate of 40 mm/h (0-10 mm/h). A computed tomography (CT) scan of the abdomen revealed no acute pathology, and a shunt x-ray series revealed no abnormalities. A CT scan of the head revealed an extradural collection crossing the midline and resolving blood products, and a crowding of the cistern. Magnetic resonance imaging of the head showed white matter changes surrounding the posterior right ventriculostomy catheter. Blood cultures were drawn and finalized with no growth. A lumbar puncture (LP) was not attempted at the time of presentation.

Physicians in the departments of neurosurgery, surgery, gastroenterology, and infectious diseases were consulted. Vancomycin and cefepime were initiated for empiric therapy of a central nervous system (CNS) bacterial infection. Improvement in leukocytosis, headache, and abdominal pain were noted after 4 days of empiric antibiotic therapy; however, the patient complained of persistent fatigue that had begun prior to hospitalization. On hospital day 5, he reported occasional chills and became febrile to 38.3 °C. On hospital day 6, an LP was performed for suspected VP shunt infection. A cerebrospinal fluid (CSF) analysis revealed a WBC count of 65 cells/mm3 (segmented neutrophils, 70%; lymphocytes, 9%; monocytes, 21%), a red blood cell (RBC) count of 29 cells/mm3, a glucose level of 63 mg/dL (serum glucose 122 mg/dL), and a protein level of 53 mg/dL. Additionally, the Gram stain revealed Gram-negative rods. The following day vancomycin was discontinued, and cefepime was escalated to meropenem due to concern for resistant organisms. On hospital day 8 the CSF culture result was finalized, with growth of pansensitive 

; the cerebellar abscess seen on CT imaging was drained. On hospital day 10 cultures from the abscess were also finalized, with pansensitive 

, and meropenem was then de-escalated to ceftriaxone.

, VP shunt infection with ventriculitis occurred; the shunt was removed and an EVD was placed on hospital day 8. A repeat LP was performed on hospital day 14 to evaluate the CSF for pleocytosis and culture clearance. A CSF analysis revealed a WBC count of 10 cells/mm3 (differential, not reported), an RBC count of 223 cells/mm3, a glucose level of 58 mg/dL (serum glucose, 100 mg/dL), and a protein level of 38 mg/dL; a Gram stain revealed no organisms. The EVD was removed the following day. Cultures from both the CSF and EVD catheter tip grew 

. CSF culture susceptibilities were reported for caspofungin, fluconazole, and voriconazole, all of which were susceptible with minimum inhibitory concentrations of 0.12 mcg/mL, 0.5 mcg/mL, and 0.12 mcg/mL, respectively.

Liposomal amphotericin B 400 mg (4 mg/kg) intravenously every 24 hours and flucytosine 2 g (30 mg/kg) orally every 6 hours were initiated on hospital day 16 for treatment of 

ventriculitis. The patient refused flucytosine doses intermittently. After 7 days of this regimen, he was transitioned to fluconazole 1200 mg (12 mg/kg) IV every 24 hours. On hospital day 42, 16 days after antifungal therapy initiation, he was transitioned to oral fluconazole 800 mg every 24 hours. The fluconazole dose was further reduced to 400 mg every 24 hours on hospital day 57 due to QTc prolongation. Fluconazole was discontinued on hospital day 64, completing 38 days of antifungal therapy. Ceftriaxone for the 

shunt infection was also discontinued at this time.

The patient experienced various complications throughout his hospital stay, including a 4-day admission to the medical intensive care unit (MICU) for intubation for airway protection, and bilateral pulmonary emboli for which he was treated with enoxaparin.Upon returning to the neurology floor from the MICU, he received physical therapy, occupational therapy, and speech therapy. He was discharged to a rehabilitation facility on hospital day 69 in stable condition.

The reported incidence of infections involving CNS drainage devices varies from 5% to 41%. Fungi account for only 2.7% of such infections in the United States, with a mortality rate of 11% to 33%.1,2 Newborns and children are most commonly affected, although adults may also develop these infections as postoperative neurosurgery complications or as disseminated disease. Neurosurgical procedures directly disrupt the blood-brain barrier, increasing its permeability and causing a reduction in immunity. This facilitates the fungi’s penetration into the CNS. In addition to neurosurgery, recent bacterial meningitis and the use of broad-spectrum antibiotics were risk factors that may have contributed to infection in the patient discussed in this case. Other risk factors for CNS candidiasis include abdominal complications and immunosuppression. Patients with these infections often present with headache, lethargy, fever, abdominal tenderness, and a change in mental status.1 Diagnosis is heavily dependent on CSF cultures. A CSF analysis may not accurately detect infection, as abnormalities could also be related to neurosurgery or the underlying indication for catheter placement.1,3,4 Normal values also may not rule out infection, as a study by Conan et al reported that 20% of adults with shunt-associated infection presented with normal CSF WBC counts and lactate concentrations.1,5

Although the Infectious Diseases Society of America developed a clinical practice guideline for the treatment of CNS candidiasis, there is limited high-quality supporting evidence. Guidelines currently recommend initial treatment with liposomal amphotericin B, with or without flucytosine.1,6 This combination works synergistically to increase fungal cell uptake of flucytosine.7-9 Therapy is subsequently transitioned to oral fluconazole after patients exhibit clinical improvement.6 Fluconazole achieves higher CSF concentrations and CSF to plasma ratios compared with other azole agents;1,7,8 however, it is not recommended in the first line as monotherapy because therapeutic failure has been documented.1,10-13 Avoiding the use of itraconazole and posaconazole for CNS candidiasis is recommended due to inadequate CNS penetration.1,6,7 Echinocandins also are not recommended because of findings from a pharmacokinetic study in a rabbit model demonstrating low CSF concentrations of micafungin.1,6,14 Results of animal studies may not translate to clinical outcomes in humans, but data on the use of echinocandins for CNS infections in humans are lacking.

Current literature describing CNS fungal infections reports varying results without a clearly defined treatment duration. Notably, this patient received 1 week of amphotericin B plus flucytosine prior to stepping down to fluconazole, which is inconsistent with the guideline recommendation suggesting that several weeks of initial amphotericin B plus flucytosine may be necessary.1,6 Based on the evidence available, the impact of early step-down to an azole is unclear. Additionally, it is not clear whether the approximate 6-week total of antifungals the patient received is adequate for cure. In a case series describing therapy for 

 CNS infections in 10 patients, 8 were treated with various combinations of amphotericin B, flucytosine, and fluconazole, with treatment durations ranging from 14 days to 2 months.7 At the time the patient in this case completed therapy and was discharged, his neurologic status had improved, his WBC count was within normal limits, and he denied headache, fever, abdominal pain, nausea, and vomiting. Although it is prudent to evaluate the pharmacokinetic literature and case studies in addition to guideline recommendations to direct therapy for patients with CNS candidiasis, further clinical data will assist in optimizing treatment regimens and defining an adequate duration.

Tunkel AR, Hasbun R, Bhimraj A, et al. 2017 Infectious Diseases Society of America’s Clinical Practice Guidelines for Healthcare-Associated Ventriculitis and Meningitis. 

Hasbun R, Rosenthal N, Balada-Llasat, et al. Epidemiology of Meningitis and Encephalitis in the United States, 2011-2014. 

Forgacs P, Geyer CA, Freidberg SR. Characterization of chemical meningitis after neurological surgery. 

Schade RP, Schinkel J, Roelandse FW, et al. Lack of value of routine analysis of cerebrospinal fluid for prediction and diagnosis of external drainage-related bacterial meningitis. 

Conen A, Walti LN, Merlo A, Fluckiger U, Battegay M, Trampuz A. Characteristics and treatment outcome of cerebrospinal fluid shunt-associated infections in adults: a retrospective analysis over an 11-year period. 

Pappas PG, Kaffman CA, Andes DR, et al. Clinical Practice Guideline for the Management of Candidiasis: 2016 Update by the Infectious Diseases Society of America. 

Bellmann R, Smuszkiewicz P. Pharmacokinetics of antifungal drugs: practical implications for optimized treatment of patients. 

Coulter KS, Bariola JR. Current Antifungal Agents for Treatment of Central Nervous System Infections. 

Medoff G, Kobayashi GS, Kwan CN, et al. Potentiation of Rifampicin and 5-Fluorocytosine as Antifungal Antibiotics by Amphotericin B. 

Sanchez-Portocarrero J, Perez-Cecilia E, Corral O, et al. The central nervous system and infection by Candida species. 

Chen TL, Chen HP, Fung CP, et al. Clinical characteristics, treatment and prognostic factors of candidal meningitis in a teaching hospital in Taiwan. 

Aleixo MJ, Caldeira L, Ferreira ML. Candida albicans meningitis: clinical case. 

Epelbaum S, Laurent C, Morin G, Berquin P, Piussan C. Failure of fluconazole treatment in Candida meningitis. 

Hope WW, Mickiene D, Petraitis V, et al. The pharmacokinetics and pharmacodynamics of micafungin in experimental hematogenous Candida meningoencephalitis: implications for echinocandin therapy in neonates. 

Chen M, Chen C, Yang Q, et al. Candida meningitis in neurosurgical patients: a single-institute study of nine cases over 7 years. 

Geers TA, Gordon SM. Clinical Significance of Candida species Isolated from Cerebrospinal Fluid Following Neurosurgery. 

Montero A, Romero J, Vargas JA, et al. Candida Infection of Cerebrospinal Fluid Shunt Devices: Report of Two Cases and Review of the Literature. 

O’Brien D, Stevens NT, Liam CH, et al. Candida infection of the central nervous system following neurosurgery: a 12-year review. 

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Rare cases of health care–associated meningitis and ventriculitis in adults caused by Candida species are associated with recent bacterial meningitis and broad-spectrum antibiotic use.

Brian Ubhaus, PharmD

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