Unusual Peritonitis: Diagnosis and Management: Mycobacterial and Fungal : Unusual Peritonitis: Diagnosis and Management: Mycobacterial and Fungal Bill Salzer University of Missouri-Columbia 2/20/07 salzerw@health.missouri.edu


Mycobacteria: Mycobacteria Tuberculosis Human pathogen- person to person via aerosol 1/3 of the world’s population is infected US- 15,000 cases/year, >50% foreign born Controlled by cell mediated immunity Non-tuberculous mycobacteria Acquired from the environment- water, soil, dust Less virulent than TB


Slide7: TB Course N Engl J Med 345:192


TB in ESRD: TB in ESRD Most active cases are reactivation disease Risk of reactivation is 5-20 fold higher than non ESRD Anergy- false negative PPD common Risk is dependent on PPD+ rate- geographical Most cases occur in 1st year on dialysis Extra-pulmonary disease in >50% Atypical presentations


TB in ESRD- Clinical Features: TB in ESRD- Clinical Features Atypical presentations common, some asymptomatic Malaise-70%, fever-70%, weight loss 50% Cough and hemoptysis- 22% Abnormal CXR- 50%, atypical patterns Extra-pulmonary- lymph nodes, pleural, miliary Peritonitis- 20%, pain, ascites, hepatomegaly Diagnosis is often delayed


TB Peritonitis in PD Patients: TB Peritonitis in PD Patients Reactivation disease, sometimes miliary Presents like bacterial- fever, pain, cloudy fluid Refractory to antibiotics, routine cultures usually – Concomitant bacterial peritonitis in 28% Peritoneal WBCs predominantly PMNs in ¾ Fluid AFB smears + in <20%, cultures only 50% + Delays in diagnosis common- mean 6weeks Delays increase mortality, catheter loss


Mycobacterial Diagnosis: Mycobacterial Diagnosis Direct smear Auramine, rhodamine- fluorescent, screen specimens Ziehl-Neelsen, Kinyoun- Acid-fast, carbol-fuchsin Cultures BACTEC- quick 1-2 weeks Solid media- Löwenstein-Jensen, Middlebrook - slow TB or not TB that is the? Biochemicals- slow DNA probes, GLC, NAP- quick MTB PCR?- smear +, 95-98% sensitive Drug susceptibility testing- old and new


TB Peritonitis in PD- Diagnosis: TB Peritonitis in PD- Diagnosis AFB fluid smears positive in < 20% AFB fluid cultures positive in only 50% PPDs positive in 50%, specificity in endemic areas? Eli-spot test? Quicker and better Promising results with direct PCR of fluid Peritoneal biopsy and cultures- nearly 100% yield Caseating granulomas on biopsy


Slide13: Elad, Y. et. al. N Engl J Med 1998;339:1382-1387 Epithelioid Granulomata with Multinucleated Giant Cells against a Background of Necrotic Lymphoid Tissue (Hematoxylin and Eosin, x400)


TB Treatment in ESRD: TB Treatment in ESRD At least 3 or 4 drugs initially INH 300mg/d + rifampin 600mg/d + pyrazinamide 25-35mg/kg TIW + quinolone +pyridoxine 100mg/d Quinolone- moxifloxacin 400mg po/d? Modify based on drug susceptibilities ?drug resistant strains Duration 6 months Catheter removal- controversial, not always required Dose modification for ethambutol, streptomycin, quinolones, PZA as above


Prevention of TB in ESRD Patients: Prevention of TB in ESRD Patients Identify and treat latent TB infections PPD skin tests for all with ESRD, early “A decision to test is a decision to treat” Induration 10mm= +, CXR to R/O active pulmonary Preventive therapy for all positives INH 300mg/d + pyridoxine 100mg for 9 months Rifampin 600 mg/d for 4 months Rifampin 300 mg/d + PZA 25-35 mg/kg TIW for 2 months Watch for hepatitis with RF+PZA regimen


Quantiferon-TB Gold: Quantiferon-TB Gold Test for latent TB infection Blood test- measures in vitro IFN-gamma production Uses ESAT-6 and CFP-10 as stimulants More specific than PPD (96-98%) in BCG pt ?more sensitive than PPD Problems Cost Availability How sensitive?


Nontuberculous Mycobacteria: Nontuberculous Mycobacteria > 100 species, 60 pathogens Runyon classification- colony, growth rate, pigment Now growth rate, molecular Environmental sources No human to human transmission Less virulent than MTB Diseases, host immune status Geography


NTM- Sources: NTM- Sources Water including, tap, nosocomial Soil Animals Aerosolized Ingested Direct inoculation- trauma, surgical MAC everywhere, Malmoense, genavense- Europe M. ulcerans- tropical swamps


Non-TB Mycobacterial PD Infections: Non-TB Mycobacterial PD Infections Environmental- soil, water, dust, direct contamination Predominantly rapid growers- M fortuitum, chelonei Contaminated machines, water, outbreaks Peritonitis, exit or tunnel infections, abscess Like bacterial- fever, pain, cloudy fluid Peritoneal WBCs usually predominantly PMNS Gram stain may show gram + rods- diphtheroids Culture negative, refractory to antibiotics


NTM- Microbiology: NTM- Microbiology Digestion, decontamination- careful AFB smear- Auramine, Kinyoun Media- Middlebrook, BACTEC, MGIT Rapid 10d, medium 7-10 Skin source- incubate at 28-30 C- marinum et al M. genavense, malmoense, ulcerans- 10-12 weeks M. Haemophilum- needs iron, cool and slow Species- HPLC, gene probes, biochemicals


Rapid Growing NTMs: Rapid Growing NTMs M. fortuitum, abscessus, chelonei Grow in abscessus>chelonei


NTBM Peritonitis- DX and RX: NTBM Peritonitis- DX and RX Gram stain may show gram + rods, AFB + Routine cultures- 2-10 days “diphtheroids” AFB cultures +- species identification takes time Peritoneal biopsy- non-caseating granulomas, culture Treatment Catheter removal usually necessary Inherently resistant to most TB drugs Clarithromycin, quinolones, doxycycline, sulfa, amikacin, tobramycin, imipenem, cefoxitin 1-2 drugs, 4-24 months duration


Slide24: Infectious Disease Clinics of North America 15: number 3 p756, 2001


Fungal Peritonitis in PD Patients: Fungal Peritonitis in PD Patients Filamentous fungi (molds) Environmental, catheter contamination, bad dx and rx Candida- yeast Endogenous flora- GI, GU, skin sources, nosocomial Risks Recent antibiotics- 65%, bacterial peritonitis- 48% Emergency PD Recent hospitalization HIV infection- 7 X risk of non-HIV Extra-peritoneal infection, abdominal surgery


Candida Peritonitis in PD: Candida Peritonitis in PD Via catheter, tunnel, or ? Ascending in women Like bacterial- fever, pain, cloudy fluid, > 75% PMNs Refractory to antibiotics Fluid gram stains reveal yeast in 50% Fluid cultures + 99% on routine media


Fungal Peritonitis Treatment: Fungal Peritonitis Treatment ISPD Guideline 2005 Remove catheter Fluconazole 200mg/d +Flucytosine 2gm X1d,then 1gm/d Duration 2-4 weeks Check antifungal susceptibilities, species Fluconazole resistant? Oral azoles- itraconazole, voriconazole, posaconazole Amphotericin B Echinocandins- caspofungin, micafungin, anidulofungin


Azole Resistance in Candida: Azole Resistance in Candida Fluconazole C albicans is the most susceptible species Tropicalis>parapsilosis>> glabrata, krusei Non-albicans species increasing in nosocomial Fluconazole failure related to species Check species, drug susceptibilities if available Newer azoles are more active on these strains


Candida albicans: Candida albicans http://www.doctorfungus.org


Candidemia- Species UMC : Candidemia- Species UMC 2/02-2/03 3/03-1/04 Totals Species cases % cases% C. Parapsilosis 7 33% 1 11 21% C. Albicans 5 24% 6 32 28% C. Tropicalis 4 19% 4 21 21% C. Glabrata 4 19% 7 37 28% C. Famata 1 5% 0 2%


Slide31: Candida in vitro azoles CID 36:


Fluconazole (“Diflucan”): Fluconazole (“Diflucan”) Generic- cheap now Well absorbed po, hydrophilic (CSF, urine,perotoneum) Renal excreted- dose adjustment for renal function Active candida (?glabrata,krusei) crypto, cocci Side effects GI, headache, rash, alopecia, hepatitis Drug interactions Inhibits CYP 3A4, 2C19


Flucytosine: Flucytosine 5-fluorocytosine- fluorinated pyrimidine (1972) Fungal cytosine permease, cytosine deaminase- 5-FU Inhibits RNA synthesis, thymidylate synthetase PO 25-37.5 mg/kg q6h; renal excretion Monitor serum levels- 30-60 min post dose- 50-100ug/ml Renal insufficiency- 2grams day 1, then 1 gram/day CSF levels 74% of serum- hydrophilic Toxicity- hematological, GI- with high levels


Itraconazole (“Sporanox”): Itraconazole (“Sporanox”) PO caps, liquid (cyclodextrin); IV Absorption capsules pH dependent, liquid not Lipophilic, hepatic metabolism Activity-candida, aspergillus, histo, blasto, sporo, cocci, dermatophytes Side effects GI, liver, rash, hypokalemia, edema, BP Drug interactions Inhibits CYP3A4


Voriconazole (“Vfend”): Voriconazole (“Vfend”) Triazole antifungal, IV and PO forms Antifungal activity like itra- candida, crypto, histo, blasto, aspergillus, other filamentous Well absorbed orally, food decreases Liver metabolism- CYP- 2C19, 2C9, 3A4 Not much in urine or CSF (like itra) IV- cyclodextrin vehicle, don’t use if GFR<50 Side effects- Visual in 30% Drug interactions- sirolimus, rifamycins, statins etc


Voriconazole for Candida Peritonitis: Voriconazole for Candida Peritonitis Kleinpeter MA.AdvPeritDial 2004;20:58-61 Report of 2 cases Case 1- Exit site infection Candida species resistant to fluconazole Voriconazole po for 28 days- Success, retained cath Case 2 peritonitis Candida parapsilosis Success with cath in place


Posaconazole- “Noxafil”: Posaconazole- “Noxafil” Approved in 2006 PO, liquid suspension, take with food Activity- like voriconazole + some Zygomycetes Good activity on fluconazole resistant candida Metabolized by UDP glucuronidation Inhibits CYP-3A4 No dose adjustment for renal


Echinocandins: Echinocandins Inhibit Beta 1,5-D glucan synthase IV only Activity- candida species, aspergillus species No activity on other yeasts, ? Molds Class side effects Histamine reaction, flushing, prurutis, low BP Phlebitis Fever Mild LFT elevation


Echinocandins- Pharmacology: Echinocandins- Pharmacology Caspofungin- “Cancidas” IV 70mg day 1, subsequently 50 mg/day Hepatic metabolism, not CYP, reduce with ESLD Drug interactions- cyclosporine, tacrolimus, rifampin Micafungin- “Mycamine” IV 50-150mg/day, probably 100 Hepatic metabolism, non CYP, Anidulofungin- “Eraxis” IV day 1 200mg, subsequently 100mg/d, < 1.1mg/min Metabolized in serum- no dose adjustment


Antifungals for PD peritonitis: Antifungals for PD peritonitis Remove catheter Fluconazole empirically, ? + flucytosine Fluconazole resistant C. glabrata, krusei- assume resistan Drug susceptibility testing Itra-, vori- or posaconazole PO Amphotericin B or echinocandin IV Filamentous fungus Remove catheter Voriconazole, posaconazole, ampho B