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Where Are We? Pneumocystis Jirovecii (P The 28th ECCMID 2018 in Madrid 23 Apr 2018, 09:00-11:00, Hall R Molecular diagnosis of fungal infections: where are we? Pneumocystis jirovecii (P. jirovecii) Norihiko Goto Nagoya Daini Red Cross Hospital, Transplant Nephrology, Nagoya, Japan ESCMID eLibrary I have no financial relationships to disclose relevant to my presentation © by author In the 1980s, P. Jirovecii infection increased dramatically with the emergence of the HIV epidemic P. Jirovecii infection in non-HIV has become an increasing problem P. Jirovecii infection in HIV can be controlled by maintaining ESCMIDthe CD4 count and using eLibraryroutine prophylaxis © by authorAm J Med. 2014; 127(12): 1242.e11-7 Pneumocystis pneumonia (PCP) incidence rates in non-HIV-infected patients ESCMID eLibrary Am J Med. 2014;127(12):1242.e11-7 © by author Proportion of all P. jirovecii–associated hospital admissions and change in population rates over time (England, UK, 2000–2010) The difference in rates between the 2 periods was most marked among ESCMIDpatients who had undergone transplantation.eLibraryEmerg Infect Dis. 2013; 19(3): 386-92 47% of whom had undergone kidney transplantation during 2000–2010. © by author What is the problem in non-HIV PCP? ESCMID eLibrary © by author Non-HIV PCP presents with an abrupt onset of respiratory failure ESCMID eLibrary Emerg Infect Dis. 2014; 20(9): 1490-7 © by author Clinical management of HIV PCP and non-HIV PCP Emerg Infect Dis. 2014; 20(9): 1490-7 ESCMID eLibrary © by author Difference between HIV PCP and non-HIV PCP Non-HIV HIV Onset Sudden Slow Number of pathogen Few Many (P. jirovecii) Useful markers of CD4 cell counts No immunological status <200/mm3 Mortality High; 39% Not high; 6.6% PCP rapidly progresses, is difficult to diagnose correctly, and causes severe ESCMIDClin Med eLibrary Insights Circ Respir Pulm Med. 2015; 9( Suppl 1): 81- 90 respiratory failure with a poor prognosisTranspl in Infect non -Dis.HIV 2011; 13(6): 551-8 Chest 2000; 118 (3): 704–711. © by author Host inflammatory response and number of organisms HIV PCP Host immune response Number of P. jirovecii ESCMID eLibrary © by author Host inflammatory response and number of organisms Non-HIV PCP Number of P. jirovecii Host immune response ESCMID eLibrary © by author Mortality and host immune response Host Underlying disease Mortality immune response HIV 6.6% Weak Kidney transplantation 5-33% Collagen disease 32-33% Strong Transplantation 2009; 88 (3): 380–385 J Clin Microbiol 2008; 46 (3): 966–971 The outcome of PCP is inversely correlated withClin Infectintensity Dis 2007; of immunosuppression44 (9): 1143–1149 Transplant Proc 2009; 41 (1): 170–172 ESCMID eLibraryClin Infect Dis 2002; 34 (8): 1098 – 1107 J Rheumatol 1994; 21 (2): 246–251 © by author Adjunctive corticosteroids for severe host responses to P. jirovecii in non-HIV PCP are needed? ESCMID eLibrary © by author Adjunctive corticosteroids for non-HIV PCP Retrospective studies with small sample size Benefit Decreased mortality Chest. 1998;113:1215–1224. BMC Infect Dis. 2011;11:76. Rheumatol Int. 2009;29:1327–1330. No benefit Antimicrob Agents Chemother. 2011;55:4613–4618. Arthritis Rheum. 2009;61:305–312. Respir Res. 2013;14:87. Clin Infect Dis. 2002;35:929–934. ESCMID eLibrary © by author Impact of adjunctive corticosteroids on survival for non-HIV PCP (Systematic Review and Meta-Analysis) There was no association between corticosteroids and survival in non-HIV PCP (OR, 0.66; 95% CI, 0.38-1.15;Transplant P = 0.14 Direct.) 2017; 3(3): e137 ESCMIDBut data are limited and findings eLibrary should not be considered conclusive © by author Dose and duration of corticosteroids mg HIV PCP Cochrane Database Syst Rev 2006; 3: CD006150 100 80 50 40 20 0 150 80-120 ; 5-7days Non-HIV PCP Am J Transplant. 2013; 13(Suppl 4): 272–279 100 7-14 days 50 0 ESCMID40–60 mg of prednisone eLibrary given twice daily for 5–7 days before being tapered over a period of at least 7–14 days © by author Corticosteroids are best administered within 72 hours in the setting of hypoxia (PaO2 < 70 mmHg) Commonly used but not well studied in transplantation Am J Transplant. 2013; 13 Suppl 4: 272-9 mg 200 160 150 Our kidney Center 100 80 50 40 5 ESCMID0 eLibrary © by author Anti-pneumocystis agents for treatment Agents Dosing 15–20 mg/kg/day of the TMP component given IV in divided doses every Trimethoprim-sulfamethoxazole 6–8 hours often in combination with corticosteroids (see below); for (TMP-SMX) milder disease, two double-strength tablets can be given po bid-tid 4 mg/kg/day IV initially over 1–2 hours; dose reduction to 2–3 mg/kg/day Pentamidine isesthionate if needed Atovaquone 750 mg po bid (optimal dose uncertain; 1500 bid used anecdotally) Primaquine 15–30 mg po qd in combination with clindamycin 600–900 Primaquine and clindamycin mg IV or po q6–8 hours Dapsone 100 mg po qd used in combination with trimethoprim 15 Dapsone and trimethoprim mg/kg/day po divided tid P. Jirovecii isTrimetrexate now classified45 mg/m2/day as a fungus, IV (or not 1.5 mg/kg/daya protozoan IV in patients <50 kg) Trimetrexate with folinic acid with folinic acid 20 mg/m2 po or IV every 6 hours (80 mg/m2 total daily); But most ofFolinic themacid for therapytreatment extends are ≥antiprotozoal 3 days beyond agentstrimetrexate therapy Pyrimethamine and Pyrimethamine load of 100–200 mg po, followed by 50–100 mg po qd in sulfadiazine combination with sulfadiazine 4 g po qd in divided doses Macrolides such as clarithromycin or azithromycin in combination with Macrolide and SMX sulfamethoxazole may be synergistic in vivo (49) 70 mg IV loading dose of caspofungin on day one, followed by 50 mg IV Caspofungin ESCMIDand TMP-SMX daily after in combinationeLibrary with TMP-SMX (dose reduced in the setting of moderate to severe hepatic dysfunction) © by authorAm J Transplant. 2013; 13 Suppl 4: 272-9 Life cycle of P. jirovecii remains poorly defined Pneumocystis organisms in different mammals are quite different, and strains from one host animal do not infect other animal species P. jirovecii can only survive in the respiratory organ of human beings ESCMID eLibraryInfect Immun. 1993;61(7):2886 -90 © by authorMem Inst Oswaldo Cruz. 2009; 104(3): 419-26 Trophic forms or cyst forms? In the lungs of PCP, trophic forms are the most abundant (90%–95%) Mem Inst Oswaldo Cruz. 2009; 104(3): 419-26 Cysts are detected in the bronchial lumen Med Mycol. 2000; 38 Suppl 1: 23-32 TMP-SMX is effective for PCP (trophic forms) treatment ESCMID eLibrary © by author PCP prophylaxis is required for the poor prognosis of non-HIV PCP? ESCMID eLibrary © by author Anti-pneumocystis agents for prophylaxis Agents Dosing Trimethoprim-sulfamethoxazole Can be given at 80 mg TMP/400 mg SMX or 160 mg TMP/800 mg SMX (TMP-SMX) po (single or double strength) daily or three times weekly Dapsone 50–100 mg po qd (4,4- diaminodiphenylsulfone) Atovaquone 1500 mg po qd (as single dose) Pentamidine 300 mg administered through aerosolized nebulizer q 3–4 weeks Up to 300 mg of clindamycin po qd with 15 mg of pyrimethamine po qd Clindamycin and pyrimethamine (some clinicians have administered this regimen 3 times weekly instead of daily) 70 mg IV loading dose of caspofungin on day one, followed by 50 mg IV Caspofungin ESCMIDand TMP-SMX daily after in eLibrarycombination with TMP-SMX (dose reduced in the setting of moderate to severe hepatic dysfunction) © by authorAm J Transplant. 2013; 13 Suppl 4: 272-9 TMP/SMX prophylaxis is highly effective for prevention of PCP In patients with or without HIV For PCP prevention, prophylactic TMP/SMX should be considered ESCMIDwhen the risk of eLibraryPCP is moreCochrane than Database 6.2%. Syst Rev. 2014; 10: CD005590 © by author What are clinical conditions in which the rates of PCP for patients not receiving prophylaxis might be above 6.2%? Allogeneic bone marrow transplantation, during the six months post- transplantation and afterwards with continued immunosuppression Solid organ transplantation, in the first six months after transplantation Acute lymphoblastic leukemia During outbreaks of PCP among immunocompromised patients the incidence of PCP might be high enough to justify prophylaxis Clin Microbiol Rev. 2004; 17(4): 770-82 ESCMID eLibraryCochrane Database Syst Rev. 2014; 10: CD005590 © by author Changing timeline of infection after organ transplantation Nosocomial, technical Activation of latent infection Donor-Derived Community-acquired Infection (donor or recipient) (relapsed, residual, opportunistic) Dynamic assessment of risk of infection Transplantation Common Infections in Solid-Organ Transplant Recipients Recipient-Derived <1Month 1–6Months >6Months Infection Infection with antimicrobial resistant With PCP and antiviral (CMV,HBV) Community-acquired pneumonia, species: prophylaxis: urinary tract infection MRSA Polyomavirus BK infection, Infection with aspergillus, atypical VRE nephropathy molds, mucor species Candida species (non-albicans) C. difficile colitis Infection with nocardia, rhodococcus Aspiration HCV infection species Catheter infection Adenovirus infection, influenza Late viral infections: Wound infection Cryptococcus neoformans infection CMV infection (colitis and retinitis) Anastomotic leaks and ischemia Mycobacterium tuberculosis infection Hepatitis (HBV, HCV) Clostridium difficile colitis Anastomotic complications HSV encephalitis Donor-derived infection (uncommon): Without prophylaxis: Community-acquired (SARS, HSV, LCMV, rhabdovirus Pneumocystis West Nile virus infection) (rabies), West Nile virus, Infection with herpesviruses (HSV, JC polyomavirus infection (PML) HIV,Trypanosoma cruzi VZV, CMV, EBV) Skin cancer, lymphoma (PTLD) Recipient-derived infection HBV infection (colonization): Infection with listeria, nocardia, Aspergillus, pseudomonas toxoplasma, strongyloides, leishmania, ESCMID eLibraryT. cruzi © by authorN Engl J Med. 2007; 357(25): 2601-14 Primary prevention of PCP after solid transplantation PCP prophylaxis for At least 4 months in the EBPG guidelines Nephrol Dial Transplant.
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