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Cryptococcal Meningitis Patient Case Presentation : 

Cryptococcal Meningitis Patient Case Presentation Rohit Jolly PharmD Candidate 2009 Ernest Mario School of Pharmacy Rutgers University Wednesday, March 11, 2009

Presentation Overview : 

Presentation Overview Patient case Cryptococcus disease background Epidemiology and Etiology Causes & Risk Factors Clinical presentation Testing and Diagnosis Treatment

Patient Information : 

Patient Information 50 year old Black female Allergies: NKDA PMH: Myocardial Infarction, Hypertension, AIDS (noncompliant), Anxiety, Coronary Artery Disease (EF=65%), Irregular Menses PSH: Bare metal stent placed 9/2008, Partial colon resection

Prior Medications : 

Prior Medications Labetolol 200mg po BID Zocor® (simvastatin) 40mg po QHS Aspirin 81mg po Daily Plavix® (clopidigrel) 75mg po Daily Apresoline® (hydralazine) 10mg IV Q8h Percocet® PRN for pain

Social History : 

Social History EtOH- 2 beers/week Smoker- 1 PPD X 35yrs Cocaine usage MW is unemployed and lives alone.

History of Present Illness : 

History of Present Illness MW is a 50 year old black female presenting with cough, fevers, dyspnea, SOB, dizzy spells, and headaches. No chest pain. She was previously discharged last week after being admitted for cough, fever, SOB. Weight: 71.3kg Vitals: 98.3°F RR:18 HR:86 BP:114/76 CrCl= 60.6ml/min 137 106 4.0 24 13 1.25 120 9.0 27.0 2.5 72

Infectious Disease Consult : 

Infectious Disease Consult Date of Consult: February 24, 2009 Reason of Consult: Attending uncomfortable treating cryptococcal meningitis in an HIV + patient Patient sent from ATEAM nursery staff on 2/12/09 to ER Diagnosed with cryptococcal meningitis on 2/16/09 All future orders for crypto and antiretroviral treatment

Cultures : 

Cultures 2/16 CSF Gram stain, some WBC + India ink test Cryptococcus antigen >256 2/18 CSF Heavy yeast + 2/25 CSF Moderate Cryptococcus neoformans 1:256

Cultures : 

Cultures 2/2-3 Blood Negative 2/2 Urine 25k mixed flora >3 organisms 2/2 Nasopharynx RSV undetected Influenza A/B undetected

Procedures : 

Procedures 2/21 Transfused 2 units PRBC for anemia (HGB 8.6) 2° to menorrhagia or dilution from fluids? 2/24 Transfused 2 units platelets (PLT 77) Need PLT> 100,000 in order to lumbar puncture Risk for spinal/epidural bleed Can cause headaches and nausea 2/25 Lumbar puncture performed 2/25 Transfused 2 units PRBC for anemia (HGB 7.9)

Pertinent Findings : 

Pertinent Findings CT scan: dilated ventricles CSF pressure >36cm H2O Cryptococcus antigen (+): 2/16/09 > 256 2/25/09 1:256 CSF values: 2/16/09 glucose: 44 Total protein: 34 WBC: 11 RBC: 3 2/25/09 glucose: 40 Total protein: 57 WBC: 36 RBC: 19 CD4 count: 2/18/09 4 cells/µL WBC count: 2/14/09 3.8k 2/26/09 2.2k

Current Medications : 

Current Medications Diazepam (Valium®) 2/14-2/27 2mg po q12h for anxiety Famotidine (Pepcid®) 2/14-2/27 20mg po daily for GI prophylaxis Metoprolol (Lopressor®) 2/17-2/27 25 mg po q12h for htn Clopidogrel (Plavix®) 2/13-2/27 75mg po daily for stent Hydralazine 2/14-2/25 10mg IV q8h prn for htn Simvastatin (Zocor®) 2/12-2/27 40mg po QHS Aspirin 2/16-2/27 81mg po daily Ramipril (Altace®) 2/17-2/27 5mg po daily Meperidine (Demerol®) 2/20-2/27 25mg IV daily prn for chills/rigors Normal Saline 2/18-2/25 100mL/hr for 5 hours

Current Medications : 

Current Medications Sulfamethoxazole/TMP (Bactrim DS®) 2/17-3/17 800/160mg po daily Azithromycin (Zithromax®) 2/19-3/02 600mg po daily M-Th Amphotericin B 2/16-2/27 50mg IV daily (83.33mL/hr for 6 hrs) Flucytosine (Ancobon®) 2/16-2/22 1500mg po q6h Fluconazole (Diflucan®) 2/27 800mg po daily

Meningitis : 

Meningitis Inflammation of membranes surrounding the brain and spinal cord Most common pathogens: Streptococcus pneumonia Haemophilus influenza http://bayloraids.org/atlas/32.htm

Background on Cryptococcus : 

Background on Cryptococcus Serious and potentially fatal infection caused by the fungus Cryptococcus neoformans Encapsulated yeast-like fungus Found in soil and bird droppings around the world Species consist of serotypes A thru D Serotypes A and D (C. neoformans var neoformans) typically seen in immunocompromised patients Serotypes B and C (C. neoformans var gatti) typically seen in normal patients

Etiology : 

Etiology Isolated from eucalyptus trees in tropical and sub-tropical regions Found in northwest regions of United States Commonly spread through bird droppings (pigeons) and bats Requires inhalation of airborne fungi

Epidemiology : 

Epidemiology Cryptococcus for: Prior to ART 5-8% of AIDS patients developed Cryptococcus infection Incidence decreasing in recent years in United States Occurs in 5 out of every 1 million people Rarely seen in children Men affected 3x more than women

Risk Factors : 

Risk Factors Immunosuppressed patients with CD4 count <50-100 AIDS (Opportunistic infection) Cancer patients CLL, lymphoma, HSCT Sarcoidosis Long-term corticosteroid therapy Organ transplant

Presentation : 

Presentation Clinical Presentation Pulmonary Cryptococcus (Most common) Cough, fever, shortness of breath, hemoptysis lobular infiltrates. CNS (second common) Acute Headache, fever, memory loss, nuchal rigidity Chronic Headache, altered mental status Cutaneous (sign of dissemination) Papules, tumors, vesicles, plaques, abscesses, cellulitis, purpura, ulcer, bullae, or subcutaneous swelling Painless nodules

Signs and Symptoms : 

Signs and Symptoms Cryptococcal meningitis Frontal or temporal headache (80-95%) Fever (60-80%) Lethargy, memory loss, mental status changes Photophobia (80%) Stiff neck

Complications : 

Complications Early death correlates to increased ICP Obstructive hydrocephalus When CSF is not properly drained: Severe headache and nausea are signs Blurry vision Could cause brain damage, coma, death

Testing and Diagnosis : 

Testing and Diagnosis AIDS patients require lumbar puncture to rule out CNS disease CT of brain India Ink 2hrs turnaround Sensitive to 30-50% in non-AIDS patients Sensitive to 80% in AIDS patients

Testing and Diagnosis : 

Testing and Diagnosis Cryptococcus antigen testing Single most useful test (Sensitive up to 95%) Can be performed on blood or CSF fluid Differential Diagnosis Toxoplasmosis Lymphoma AIDS dementia complex Progressive multifocal Herpes encephalitis Other fungal disease

Poor prognosis : 

Poor prognosis + India Ink Increased ICP pressure Decreased CSF glucose CSF leukocyte count <20cells/uL Cryptococcus antigen >1:1024

Good prognosis : 

Good prognosis Normal mental status Headache as a symptom CSF leukocytes >20cells/uL Underlying disease process

Treatment in HIV + Patients : 

Treatment in HIV + Patients First-Line [Amphotericin B (0.7- 1 mg/kg/d IV) or L-AMB] + flucystosine (100 mg/kg/d po in 4 doses) x 2 wks Follow up with fluconazole 400 mg po daily for 10 weeks minimum May reduce fluconazole dose to 200 mg po daily thereafter and continue for life Alternative [Amphotericin B (0.7- 1 mg/kg/d IV) or L-AMB] + flucystosine (100 mg/kg/d) x 6-10 wks Follow up with fluconazole 400 mg/d for maintenance therapy

Treatment in HIV + Patients : 

Treatment in HIV + Patients Second-Line Fluconazole (400-800mg/d) +flucystosine (100-150 mg/kg/d) x 6 wks Toxicity is very high with this regimen Only given if Amphotercin B can not be tolerated Precaution In all treatment regimens intracranial pressure must be monitored to ensure optimal outcome

Treatment in Immunocompetent : 

Treatment in Immunocompetent First-Line [Amphotericin B (0.7- 1 mg/kg/d IV) or L-AMB] + flucystosine (100 mg/kg/d) x 6-10 wks Alternative [Amphotericin B (0.7- 1 mg/kg/d IV) or L-AMB] + flucystosine (100 mg/kg/d) x 2 wks Follow up with fluconazole 400 mg/d for 10 weeks minimum May continue fluconazole for as long as 6-12 months

Mechanisms of Action : 

Mechanisms of Action Flucytosine (Ancobon®) Incorporates itself into fungal RNA and inhibits synthesis of DNA and RNA Amphotericin B (Abelcet®, AmBisome®) polyene binds to sterols in the cell membrane and disrupts permeability to allow leakage of cellular components Fluconazole (Diflucan®) triazole antifungal inhibits CYP450 enzyme 14a-demethylase to prevent conversion of lanosterol to ergosterol, an essential component of the fungi’s cell membrane

Adverse effects : 

Adverse effects Amphotericin B Bone marrow suppression ? anemia Permanent renal damage Hypokalemia Hypomagnesemia Fevers, chills, headache, diarrhea Fluconazole Prolong QT interval Elevated liver enzymes Nausea, vomiting, abdominal pain, diarrhea

Precautions with Amphotericin : 

Precautions with Amphotericin Pre-treat with diphenhydramine and acetaminophen to decrease fever and chill. Add heparin 500U and hydrocortisone 50mg to decrease phlebitis Hydration and sodium repletion prior to administration may reduce nephrotoxicity Infuse over 2-6 hours

Second Line Alternatives : 

Second Line Alternatives Itraconazole 1992 study compared itraconazole 200mg bid x 6 weeks to amphotericin b (0.3mg/kg/d)+ oral flucytosine (150 mk/kg/d) x 6 weeks. Not effective in complete response when used as initial therapy 1989 study compared itraconazole 200mg bid x 6 weeks to amphotericin b + oral flucytosine x 6-8 weeks. Effective and well tolerated Only 14 patients in study

Progress and Performance : 

Progress and Performance CSF opening pressure (lateral recumbent position) Sufficient CSF collection for culture (3mL) CSF cryptococcal antigen titer, glucose level, protein level, and cell count (5mL)

Pros and Cons of Flucytosine : 

Pros and Cons of Flucytosine Disadvantages: Increased bone marrow suppression Weak antifungal effects as mono therapy and fast development of resistance Bone marrow suppression and hepatotoxicity Dose related adverse events Special boxed warning for use in patients with renal dysfunction Available in 250 and 500mg capsule Requires taking many capsules @ 100mg/kg/d

Pros and Cons of Flucytosine : 

Pros and Cons of Flucytosine Advantages Synergistic activity with amphotericin B Results in fewer failures or relapses (75-80% SR in Non-HIV) More rapid sterilization of the CSF Less nephrotoxicity (allows dose reduction of amphotericin B 0.3-0.5mg/kg/d) Therapeutic levels can be monitored Trough: 25-50mcg/mL Peak: 50-100mcg/mL (drawn 2 hours after)

Pharmacokinetics : 

Pharmacokinetics 76-89% bioavailability Distributes to CSF, aqueous humor, joints, peritoneal fluid, and bronchial secretions Protein binding 3-4% 2-5 hour half-life (75-200hr if renally impaired)

Clinical Trials : 

Clinical Trials Oral versus Intravenous Flucytosine in Patients with Human Immunodeficiency Virus-Associated Cryptococcal Meningitis Antimicrobial Agents and Chemotherapy March 2007

Clinical Success : 

Clinical Success Study Design 64 adults with 1st episode randomized to one of four treatment arms. Amphotericin B (0.7 mg/kg/d) Amphotericin B (0.7 mg/kg/d) + fluconazole 400mg Amphotericin B (0.7 mg/kg/d) + flucytosine 100mg/kg/d Triple therapy Clinical efficacy was measured by serial CSF cultures and safety thru HPLC testing for flucytosine/fluorouracil concentrations in plasma and CSF.

Patient selection : 

Patient selection Inclusion criteria 1st episode of cryptococcal meningitis diagnosed by CSF India Ink and antigen tests Exclusion criteria ALT > 5x ULN Neutrophil count < 5k Platelet count <50k Pregnancy

Study Results : 

Study Results 64 patients enrolled One subject dropped (HIV -) 16 oral and 15 IV flucytosine. 32 did not receive 5-flucytosine. Early fungicidal activity was greater in combination arms (-0.46 vs. -0.34 log CFU/day) colony forming units No difference in oral vs iv (-0.43 vs. -0.48) Mortality was similar among all treatment regimens

Final Conclusion : 

Final Conclusion Flucytosine was safe at 100mg/kg/day for 2 weeks Author believes no drug concentration monitoring is required at this dose in developing country Oral formulation had lower 5-FC levels, however the 5-FU concentrations were found to be higher. Suggestive of intestinal flora’s role in conversion Clinical application: Obtaining flucytosine drug levels may be appropriate for neutropenic patients as variability exists in the bioavailability of the oral dose.

References : 

References ICN Pharmaceuticals. Ancobon® package insert. Costa Mesa, CA; 2003. Bennett JE, Dismukes W, Duma RJ, et al. A comparison of amphotericin B alone and combined with flucytosine in the treatment of cryptococcal meningitis. N Engl J Med 1979;301:126–31. Denning DW, Tucker RM, Hanson LH, et al. Itraconazole therapy for cryptococcal meningitis and cryptococcosis. Arch Intern Med 1989;149:2301–8. van der Horst C, Saag MS, Cloud GA, et al. Treatment of cryptococcal meningitis associated with the acquired immunodeficiency syndrome. N Engl J Med 1997;337:15–21.

References : 

References Larsen RA, Leal MAE, Chan LS. Fluconazole compared with amphotericin B plus flucytosine for the treatment of cryptococcal meningitis in AIDS: a randomized trial. Ann Intern Med 1990;113:183–7. de Gans J, Portegies P, Tiessens G, et al. Itraconazole compared with amphotericin B plus flucytosine in AIDS patients with cryptococcal meningitis. AIDS 1992;6:185–90. Saag MS, Graybill RJ, Larsen RA. GUIDELINES FROM THE INFECTIOUS DISEASES SOCIETY OF AMERICA: Practice Guidelines for the Management of Cryptococcal Disease. Clinical Infectious Diseases 2000;30:710–718 http://www.cdc.gov/nczved/dfbmd/disease_listing/cryptococcus_gi.html http://www.atdn.org Ropper AH, Brown RH, "Chapter 32. Infections of the Nervous System (Bacterial, Fungal, Spirochetal, Parasitic) and Sarcoidosis" (Chapter)