Accepted Article Conflictsof interest: authors The no conflicts report ofinterest relevant to thismanuscript. [email protected] Boston, MA, 02114 55 Fruit Street WH510A Center Transplant MGH M.D. Fishman, Jay A Author: #Corresponding [email protected] USA. CA, Alto, Paolo University, Stanford Hosts, Immunocompromised for Program Diseases Infectious Pediatric Medicine, of * Professor [email protected] USA. MA, Boston, School, Medical Harvard and Hospital General This by is protectedarticle reserved. Allrights copyright. doi: 10.1111/ctr.13587 lead to differences between this version and the throughbeen the copyediting, pagination typesetting, which process, may and proofreading hasThis article been accepted publicationfor andundergone peerfull but review not has + JayFishman, A. M.D. Practice of Community Diseases Infectious Transplantation jiroveci Pneumocystis Infectious Issue-Transplant Diseases :Special Article type DR. JAY A.FISHMAN (Orcid ID:0000-0002-2671-3311) Community Practice of Professor of Medicine, Transplant Infectious Infectious Transplant Medicine, of Professor +# in Solid Transplantation Solid Organ in and Hayley Gans, M.D.* on behalf of the AST InfectiousDiseases Diseases and Transplant Center, Massachusetts Version of Record. Please Version as this cite ofRecord. article - Guidelines Society theAmerican from of

Accepted Article prophylaxis an organ solid including patients immunocompromised organ transplant recipients recipients transplant organ transplantation, This by is protectedarticle reserved. Allrights copyright. processes seenbest by scans. CT Patients generally have PO interstitial diffuse reveal generally patterns radiographic Chest cough. and hypoxemia, with corticosteroids, and advancing Presentation patient age (>65). typically includes fever, dyspnea or rejection graft treated hypogammaglobulinemia, (CMV), infection cytomegalovirus counts, lymphocyte low include factors Risk later. develop may but organ transplantation sulfamethoxazole (TMP-SMX). Without prophylaxis,PJP risk isgreatest in the 6monthsfirst after not should PJP recipients. transplant among described been have infection of clusters Nosocomial infection. prior of reactivation or transmission jiroveci of management and prevention diagnosis, the review Transplantation of Society American the of Practice of Community Diseases Infectious the from guidelines updated These Abstract in the setting of atypical presentations or incompletely effective prophylaxis. Pneumocystis jiroveci Pneumocystis Introduction TMP-SMX. with preferably posttransplant, months 6-12 least at for recommended is prophylaxis PJP Routine early. be useful may to resorting before documented be should allergy Quantitative PCR adjunct useful isa todiagnosis. is TMP-SMX drugchoicethe of for therapy; drug respiratory specimens with direct (1 serum elevated and (LDH), dehydrogenase fungal infection transplant recipients. (PJP) may develop via airborne airborne via develop may (PJP) Pneumonia recipients. transplant infection fungal 1-4 . With prolonged survival and increasing and survival prolonged . With Pneumocystis jiroveci , formerly 5 . Major advances include improved diagnostic assays which are useful useful are which assays diagnostic improved include advances Major . P. carinii P. immunofluorescent staining; invasi staining; immunofluorescent pneumonia remains (PJP) an importantconsideration insolid ,

remains an important opportunistic fungal pathogen in in pathogen fungal opportunistic important an remains occur during prophylaxis with trimethoprim- with prophylaxis during occur → 3) β alternative therapies.corticosteroids Adjunctive -D-glucan assay. Specific diagnosis uses ly intense immunosuppressive regimens in in regimens immunosuppressive intense ly d cellstem recipientsreceiving not effective 2 <60 mmHg,<60 serum elevated lactic ve procedures may be required. required. be may procedures ve

Pneumocystis Pneumocystis Accepted Article and the trophozoites. In the alveolus, the In trophozoites. and the surface projections,or tubular expansions, form abranching network over the surfaces of the cysts small Many cysts. developing or empty including intermediates areprobably these but described, been have forms cystic other Two sporozoites. called bodies oval intracystic pleomorphic small eight and6 3 between measures usually cyst The and filopodia. pseudopodia includes It vacuoles. and mitochondria, trophozoite, 2to5 The bodies). intracystic (or and sporozoite cyst, trophozoite, been identified: have organism the red ), rather the parasiticthan kingdom of . In and animals, humans of three forms specificity of the organism humans was renamed infected persons andthan more 200,000 cases of HIV- in community-acquired of one-fourth over causing AIDS, with associated illness animal- and human-derived organisms human-derived and animal- in epitopes antigenic unique and shared both with host the to adapts organism the glycoproteins; surface of array limited arelatively produces organism The host. the and organism the both ( fungi neonates in described 1952 as “plasmacell interstitial parasite incycle the life of was not until the 1980swhen chemotherapeutic drugs led studiesto the by Centers for Disease Control in 1970’s,(CDC) the but it This by is protectedarticle reserved. Allrights copyright. of form The cyst Organism Etiology –The polyene anti-fungal antibiotics. The surface of surface The antibiotics. anti-fungal polyene and azole the to susceptibility of lack the for accounts which denovo sterols synthesize not does different hosts and with different immune defects. immunedefects. different with and hosts different in exist differences some that likely is It postulated. been have stages cysts repeat These trophozoites and toform mature seems the that sporozoites, or cyst thedaughter from forms, todevelop emerge into trophozoites. organisms human-derived understood; incompletely cyclephagocytosis of Thelife diagnostic organism, target. asa the of and and β -1,3-glucan which mayplay roles in attachment Rhizopoda, Based on conserved mRNA sequences sequences mRNA conserved on Based 6 . The increasing incidence of PJP in patients receiving corticosteroids and and corticosteroids receiving patients in PJP of incidence increasing . The Pneumocystis Pneumocystis μ

Myxomycetes, , Schizosaccharomyces, Neurospora, Candida, Candida, Neurospora, Schizosaccharomyces, Zygomycota, Myxomycetes, in diameter. Its cell wall consists of three layers, and its cytoplasm contains up to up to contains cytoplasm its and layers, three of consists wall cell Its diameter. in μ in diameter, is either round or sickle-shaped and contains a nucleus, nucleus, a contains and sickle-shaped or round either is diameter, in P. jiroveci P. 7 cruzi . P. carinii was was first described in1909 by Chagas and again in by1910 Carinii a as Czech after the parasitologist Otto Jírovec torecognize host- Pneumocystis 8,9 gained global recognition as being the first disease-defining disease-defining first the being as recognition global gained . The cell wall contains cholesterol but no ergosterol and and no ergosterol but cholesterol contains . wall cell The pneumonitis” among malnourished children and and children malnourished among pneumonitis” . The organism was first associated with human disease disease human with associated first was organism The . P. jiroveci jiroveci P. P. jiroveci

PJP since 1979. The causing infection in are covered with glycoproteins derived from derivedfrom with glycoproteins covered are the cycle. Both sexual and asexual intermediate intermediate asexual cycle. and sexual the Both to epithelial or surfactant layers, in have been grown inconsistently in vitro. It It vitro. in inconsistently grown have been is carbohydrate-rich with glucose, mannose, mannose, glucose, with carbohydrate-rich is is identified

with the taxonomic kingdom of Pneumocystis Pneumocystis Pneumocystis growth in is is and the Accepted Article post-transplantation, PJP may emerge beyond 12 months post-transplant months 12 beyond mayemerge PJP post-transplantation, factors risk and Epidemiology possibly types, antigenic of variety tandemthe repeated subtelomeric arrays in contribute regions and tothemay generation of the have importancehuman ininfection. The a MSG large is family relatedof many genes, located in also (gp45–55) antigens other although model; rat the in immunogen humoral main the represents characterized at the glycoprotein and molecular levels.The major surface glycoprotein (MSG) havebeen antigens Surface species. host different in antigens common and unique both expresses electrophoresis and DNAsequencing; multiple strainscoexist may inany individual. can exceed 10% This by is protectedarticle reserved. Allrights copyright. therapy risk of developing infection among solid organ organ solid among infection developing of risk periods of up to150days. Based on studies prior broad to the implementationof prophylaxis, the of previously established and/or undertreated infection undertreated and/or established of previously novo de may arise disease that suggest pneumocystis de immune identified with individuals to limited that exposure occurs commonly in childhood childhood in commonly occurs exposure that suggest studies Serologic beenidentified. has disease human for reservoir environmental definitive equivalent) mg prednisone 15-20 of months 6 to (3 therapy corticosteroid with and rejection, of graft suppression suchcorticosteroids as bolus or lymphocyte-depleting antibody therapies for treatment immune intensified of periods during transplantation, lung after notably most transplantation, of risk the prophylaxis, recipients recipients transplant hepatic and renal heart, among described been have typing, molecular including rejection, and patient age graft hypogammaglobulinemia, (CMV), infection cytomegalovirus counts, lymphocyte andCD4+ total prophylaxis and immunosuppression. immunosuppression. and prophylaxis to approaches center-specific and geography transplanted, organ the with varies Incidence 24,25 Some studies suggest that suggest studies Some Different strains of PJP should not occur inpatients receiv 16-19 20,23 . In patients receiving lung or heart-lung transplants, asymptomatic isolation of isolation asymptomatic transplants, heart-lung or lung receiving patients . In , supporting interhuman transmission in hospitalthe environment with incubation . Ofnote, of patients 25% developPJP 8weeksor after lessof corticosteroid 26 . Recent reports have shown that despite effective prophylaxis for 6-12 months 6-12 for prophylaxis effective despite that shown have reports Recent . Pneumocystis 23 Pneumocystis . PJP has also complicated the syndrome of rapamycin lung, the the lung, rapamycin of syndrome the complicated also has PJP .

Pneumocystis jiroveci to evade human immune responses. responses. immune human evade to pneumonia greatestis in the 6months first after solid organ have been demonstrated using pulsed-field gel gel pulsed-field using beendemonstrated have 11 ing effective prophylaxiswith TMP-SMX transplant recipients is approximately 5-15% 5-15% approximately is recipients transplant , though symptomaticalmost disease is entirely ficits. Animal models and studies in humans of of in humans studies and models Animal ficits. via airborne transmission or from reactivation reactivation from or transmission airborne via 10,12-15 may exist in environment exist in the may . Nosocomial outbreaks of infection, 22 ; factorsrisk include low P. jiroveci jiroveci P. 10 21,22 howeverno . Without . P. jiroveci jiroveci P. 20 . Accepted Article Diagnostic Strategies This by is protectedarticle reserved. Allrights copyright. The ChestRadiograph signs typical The PJP. of and symptoms plain radiographic imaging. Corticosteroids,calcin to proportion of out byhypoxemia dominated usually weeks, 2 to 1 to up days afew of course the is but variable quite can be patients HIV-negative in PJP of progression Thesymptomatic classicallymore in In than AIDS.acute setting the of transplantation, symptoms develop often over Clinical Manifestations individuals. non-HIV-infected among PJP for factors risk described persons, malignancy to infected disease), exposure lung underlying (CMV), coinfection viral function, and counts lymphocyte and neutrophil factors, an excess overall net of state immunosuppressi sirolimus-based immune suppression. PJP infection in idiosyncraticdiffuse syndrome of pulmonary infiltrates insolid organ transplant recipients receiving computed tomography (CT) often demonstrate abnormalities not appreciated on routine chest chest routine on appreciated not abnormalities demonstrate often (CT) tomography computed theseev of combinations and infection (PJP, CMV), largely or solely in the lobes upper cheston radiog cavities. Breakthrough inpatients rece disease consolidations. or lobar lymphadenopathy, patterns are common including nodules, unilateral in Unusual days. 5 to 3 over consolidation progressive with therapy despite progresses often pattern butterfly pattern; from hilar the region, infiltratesoftenthe spread tothe orapices bases. This diffus perihilar, bilateral, byfine, manifested is PJP Early infection. of duration and immunosuppression, of state disease, accompanying or underlying failure arte lower with PJP, more HIV-negative in severe present. In addition rapid onset, more the to inconsistently is latter the but cough, nonproductive by accompanied often majority the in dyspnea significant sputum production sputum significant interstitial processes onchest radiograph presents with that hypoxemia fever, withoutbut and 18,23 No radiographic pattern is pathognomonic for for pathognomonic is pattern radiographic No

.

28 . The radiographic pattern ultimately depends on the patient’sradiographicthe . The ultimatelydepends pattern on andare symptoms outlined inTable 2 P. jiroveci resulting pneumonia and lung involvement is often iving aerosolized classically presents presents classically pentamidine aerosolized iving on engendered by multiple factors (metabolic (metabolic factors multiple by on engendered rial-oxygen tension and more frequent respiratory respiratory more frequent and tension rial-oxygen eurin inhibitors, and sirolimusmay mask the signs raph. Inlung transplant patients, graft rejection, e infiltrates that progress that e infiltrates interstitialto an alveolar ents can produce similar chest radiographs. Chest chest radiographs. similar ents can produce ,or HIV infection. outlines Table 1 well-some filtrates, pleural effusions, pneumothoraces, can superinfect fungal or mycobacterial mycobacterial or fungal superinfect can persons thesecategories in not should suggest Pneumocystis Pneumocystis infection. PJP is a diffuse diffuse a is PJP infection. 27 and include fever, fever, include and Accepted Article 37 This by is protectedarticle reserved. Allrights copyright. presentation clinical consistent a with radiographs chest plain normal of face the in notably obtained, be should and radiography sensitivity (>90%) with specificity lower (less than 80%) and poor tracking with disease resolution detected with in of patients the serum PJP. serumThe (1 successful Theangiotensin-converting therapy. infection dueto infection pulmonary exclude generally will scan normal a except pneumocystosis of pulmonary diagnosis respiratory tract secretions (Table 3) Microbiology disease. acute in sensitivity andlow patients immunosuppressed many in production antibody inadequate by be complicated in the alveolus. Calcofluor white and silver st silver and white Calcofluor alveolus. in the detect intracysticbodies, orsporozoites, and trophozoites,common most the organism formof the stains Diff-Quik or Wright’s Giemsa, burden. organism ofthe 5-10% represent which wall cyst the only stain methenamine-silver orGomori O blue Toluidine specimen. the of portion nonpurulent mucoid, the from prepared are Smears hydration. oral after or water, or saline hypertonic aerosolized to exposure of minutes 30 to 20 after collected maybe sputum Induced biopsy. lung open or transbronchial and induced) or (spontaneous sputum (BAL), lavage alveolar bronchial IU/ml) 300 (over PJP of cases all almost in elevated be will enzyme (LDH) dehydrogenase lactic serum individuals with PJP with individuals infected HIV in studies on based therapy corticosteroid adjunctive of use for be anindication rise; gradients over mmHg30 at the start of therapy are associatedwith ahigh mortality (and may (Table 3). In general, patient the will have aPO Laboratory Evaluation monoclonal antibody staining is not available not is staining antibody monoclonal . However, the (1 31 . Themarked hypoxemiaofPJP is accompanied by an alveolar-arterial PAO

A definitive diagnosis of PJP is made by demonstration of organisms in lung tissue or tissue lung in organisms of by demonstration made is PJP of diagnosis A definitive Nonspecific indicators of pulmonary processes are useful in the presumptive diagnosis of PJP PJP of diagnosis presumptive the in useful are processes pulmonary of indicators Nonspecific Pneumocystis → 32 3) ). Both LDH and the arterial oxygenation gradient will return to normal with with normal to return will gradient oxygenation arterial the and LDH Both ). β -D-glucan assay has a high negative predictive value. Serologic testing may may testing Serologic value. predictive negative high a has assay -D-glucan . Abnormal PET scan images may be observed early in disease. early may beobserved in disease. images scan PET Abnormal . 29,30 . Nuclear medicine scans are nonspecific and add little to the the to little add and nonspecific are scans medicine . Nuclear 38,39 . Acceptableinclude samplesobtained specimens through ains are most predictive most are ains 38 . 2 enzyme (ACE)level(also non-specific)enzyme can be lessthan 60mmHg and arespiratory alkalosis. The → 3) 3) β -D-glucan assay carries a high for routine use when use for routine 2 –PaO 2 gradient gradient 33- Accepted Article individuals and in investigation of outbreaks of PJP including among organ transplant recipients recipients transplant organ among including PJP of outbreaks of investigation in and individuals we arenot Theseassays fungal infections. with BAL with induce of sensitivity The procedures. diagnostic This by is protectedarticle reserved. Allrights copyright. 9,43,46 glucan assay assay glucan (1 the including modalities other with often specimens), induced than (better BAL samples colonization and infection. Increasingly, paradigms are used with real-time quantitative PCR with detection with some inloss specificity, limiting the ability todistinguish between asymptomatic PJP exclude to used be cannot specimen respiratory single any from smear negative A 3). (Table institution conditio clinical the on depends test specific the of choice The required. be may biopsy lung open or lesions), mass or cystic accessible (for aspiration microbiological diagnosis 3). (Table BAL (with biopsies if possible), radiologicallyguided needle a without pneumonia with recipients transplant in considered be should diagnosis Invasive present. is disease diffuse if lobes upper the from performed be should Lavage yield. higher a have BAL may s PJP, with host infected non-HIV the in lower should BAL examination, sputum induced undergo P. jiroveci presence of apparent resistance and DHPS mutations DHPS mutations and resistance presence apparent of however, is this rarely important clinically given clinical response tofull dose TMP-SMX even in the of macrophages inflammatoryand cells. Atthe time, same alveolar the interstitium infiltrated is by debris and lungs, the from exudate proteinaceous glycoprotein, of surface amounts large organisms, a foamy eosinophilic exudate and appear honeycombed; the intra-alveolar exudate consists of HistopathologyInvasive and Diagnosis been validated. validated NATassays are likely to PJP have unlikely tohave PJP. Conversely, transplant patients withcompatible andsyndromes positive, , 13,16,17,47 NAT has been used to demonstrate the presence of multiple multiple of presence the demonstrate to used been has NAT Specimen choice considerations include diagnostic sensitivity and the invasiveness of of invasiveness the and sensitivity diagnostic include considerations choice Specimen Early nucleic acid amplification (NAT) techniques increased the sensitivity of of sensitivity the increased techniques (NAT) amplification acid Early nucleic The 18,23 is preferred as an initial step, followed more by invasive testing.children In not able to .

histopathology of histopathology . An induced sputum examination coupled with direct immunofluorescent staining for for staining immunofluorescent direct with coupled examination sputum induced . An NAT assays may be adapted to the detection of dihydropteroate synthase mutations; mutations; synthase dihydropteroate of detection the to adapted may be assays NAT 40-42 . In general, patients with low LDH or low serum (1 serum low or LDH low with patients Ingeneral, . Pneumocystis 1,43-45 ll studied in solid organ recipients. recipients. organ solid in studied ll -infected lung is distinctive. The airspaces are filled with with filled are Theairspaces distinctive. is lung -infected putum may be less revealing and bronchoscopy with with bronchoscopy and revealing be less may putum . Positive. d sputum isonly 30-55%,compared with 80-95% n of the patient the ex and of the n be performed. Because Because be performed. 48 . of Use NATwith blood samples has yet not β -D-glucan assays do not exclude other → Pneumocystis 3) 3) β -D-glucan levels are are levels -D-glucan pertise available at the the organism burden is is burden organism the strains in infected Pneumocystis → 3) β -D-

Accepted Article • This by is protectedarticle reserved. Allrights copyright. • • • • therapy. effe side and undesirable medications inappropriate common. is lungs the within disease of distribution inthe Patchiness lymphocytes. and leukocytes polymorphonuclear infected individuals, the studies in non-HIV PJP infections are contradictory are infections PJP non-HIV in studies the individuals, infected cyst form theof organism.While adjunctive corticosteroids show a survival advantage in HIV the only against effective are Echinocandins necrosis. cell forislet potential the of because recipients transplant pancreas in it avoiding recommend experts Most 4). (Table disturbances electrolyte includingpancreatitis, hypo- and hyperglycemia,bone marrow suppression, renal failure and second-line agent after TMP-SMX. Pentamidine therapy can complicatedbe by numerous toxicities the remains probably pentamidine intravenous infections, severe In TMP-SMX. than outcomes better have to shown been has agent No choice. of drug and agent line first the as of TMP-SMX 4. Practice recommendations regarding treatment the of PJP transplant in recipients include the use Treatment • hours of initiating antimicrobial therapy. The optimal dose of corticosteroids has not been been not has corticosteroids of dose optimal The therapy. antimicrobial of initiating hours within 72 ideally benefit, maximum earlyfor considered should be therapy selected. Corticosteroid re but are controversial corticosteroids remains poor outcomes, in patients with hypoxemia (pAO hypoxemia with patients in outcomes, poor

immunofluorescent staining for for staining immunofluorescent direct with coupled examination sputum induced using attempted be should diagnosis Initial tract secretions by demonstr made is PJP of diagnosis A definitive validated NATassays are likely to PJP (strong,have low) positive, and syndromes compatible with patients Transplant challenging. remains disease for specificity but diagnosis to adjuncts be useful may assays (NAT) amplification acid Nucleic , low). and elevated serum (1 (LDH), dehydrogenase lactic serum elevated hypoxia, including useful are indicators Nonspecific processes other by complicated often is Radiography for pathognomonic is pattern radiographic no since diagnosis a make to used be not should alone Radiographs diagnosis (strong , moderate). moderate). , (strong diagnosis children) orunrevealing and intransplant recipients with pneumoniawithout a microbiological younger in case the is (as feasible not sputum induced if considered be should diagnosis Invasive Attempts to avoid the use of invasive procedures by resorting to empiric therapy risks risks therapy empiric to byresorting procedures of invasive use the avoid to Attempts For the established or presumed diagnosis of PJP, therapeutic options are outlined in Table Table in outlined are options therapeutic PJP, of diagnosis orpresumed established the For Pneumocystis Pneumocystis → 3) β -D-glucan assay, which carry a high negative predictive value (strong value predictive negative high a carry which assay, -D-glucan P. jiroveci P. infection and unusual patterns are common. (strong, high). high). (strong, common. are patterns unusual and infection (strong, moderate). commended regardless of the antimicrobial agent antimicrobial agent regardlessofcommended the 2 < 70mmHg on room air), use of adjunctive adjunctive of use air), room on 70mmHg < cts, missing coinfections, and delaying effective effective delaying and coinfections, missing cts, ation of organisms in lung tissue or respiratory 22,49,50 . However, given given However, . Accepted Article a threshold for using prophylaxis prophylaxis using for a threshold centers. Historically, an incidence of at least 3-5% This by is protectedarticle reserved. Allrights copyright. burdens infectious low despite therapy of days 21 versus 14 with relapse of risk greater a have who individuals infected HIV in studies and disease, of severity therapy, to response on based required often are courses longer though days, 14 least at be should however population, this in this established fully been not has therapy antimicrobial of duration The pneumonitis. rebound avoid to recommended is days over 7-14 tapering gradual before days 5-7 for children in daily twice 1mg/kg and daily times three to two given in adults equivalent) (or prednisone of mg 40-60 but established, Routine Prevention anti- • for at least 2 weeks), prolonged neutropenia, or flares of autoimmune disease, continued or or continued disease, autoimmune of flares or neutropenia, prolonged weeks), 2 least for at rejection, infectionwith CMV, higher-dosecorticosteroid therapy (e.g. >20 mg dailyof prednisone • • • • immunosuppressant regimens, the incidence post-tra incidence the regimens, immunosuppressant 0.3 to 2.5% based on the presence of CMV in pulmonary secretions alone alone secretions in pulmonary of CMV presence the on based necessitate antiviral therapy; generally CMV is de may pneumonitis (CMV) cytomegalovirus Simultaneous presentations. atypical or therapy trials. clinical to subjected been not have immunosuppression of andreduction CSF) GM- or (G- factors stimulating colony as such measures Adjunctive relapse. and progression disease avoid to preferred is days 21 disease, mild support work initial and presentation clinical the unless

required (strong, low). low). (strong, required often are courses longer days; 14 least beat should therapy of antimicrobial The duration of hypoxia (pAO of hypoxia setting the in presentation of hours 72 within administered best are corticosteroids Adjunctive moderate) (strong, recipients. pancreas in beavoided generally should and disturbances electrolyte and hyperglycemia, and hypo- pancreatitis, cause may therapy Pentamidine high). (strong, clindamycin and primaquine atovaquone, Alternative agents are less effective and include intravenous pentamidine isethionate, high). (strong, PJP for documented choice of drug and is thefirstlinetherapeutic agent Trimethoprim-sulfamethoxazole (TMP-SMX)

Coinfection with otherpathogensconsideration a is the setting in response of poor to 23,52,53

. those who For have risk factors such as intensive the immunosuppression for graft 2 Pneumocystis < 70mmHg) (strong, low). 51 prophylaxis is generally reco generally is prophylaxis . Now with widespread use of prophylaxis and changing changing and prophylaxis of use widespread with . Now tected by blood studies and cannot be diagnosed diagnosed be cannot and studies blood by tected of PJP among transplant transplant among PJP of nsplant is uncertain but appears to range from from range to appears but uncertain is nsplant 5 , 2 mmended at most transplant transplant most at mmended . recipients was considered was considered recipients 27 . Thus,. Accepted Article This by is protectedarticle reserved. Allrights copyright. recipientsconsideredPJP high riskfor at are transplant Lung susceptibility. increased of periods for indicated generally is prophylaxis reinstituted may also be an effective agent at prophylaxis for for prophylaxis at effective agent an may be also use have includedcombination itin with pyrimethamine at mg 25-50 onceweekly, which function. renal true reflect necessarily not does that creatinine serum of elevation with hyperkalemia, in resulting secretion creatinine and potassium inhibit to capacity the has Trimethoprim pancreatitis. and meningitis, aseptic nephritis, interstitial syndrom Stevens-Johnson to reactions from benign and occur may suppression marrow monitoring. Bone TMP-SMX require Thesideeffects of occur can Rash agents. myelosuppressive other of administration concomitant by be potentiated pathogens, gastrointestinal infections, and urinary some tract pathogens. gondii is example cited commonly most The transplantation. after pathogens opportunistic other preventing at effective of being advantage potential the also has TMP-SMX TMP-SMX. to compared overall favorable as not are that issues efficacy and cost, intolerances, drug due to prophylactic other All PJP. of prophylaxis for choice be acute transplant, after occurring the firstfew weeks in than rather after 1 month. corticosteroids pre-transplant (ascase in ofthe Fo disease. onset late for as risk that shift or prolong may above outlined features though post-transplant, months 6 first the within highest immunosuppression on depending well, as transplantation liver and heart of setting the in experts bysome recommended is prophylaxis Lifelong indicated. often is prophylaxis lifelong infection, PJP prior of history a with patient transplant any as well as recipients, prophylaxis. Although it may be tolerated in transplant patients who cannot receive TMP-SMX, it is is it TMP-SMX, receive cannot who patients intransplant tolerated be may it Although prophylaxis. PJP for besufficient may dapsone with Monotherapy desired. is organisms both for prophylaxis including desquamation, neutropeni desquamation, including do have who those in recommended not generally recipients at months leastfor 6-12 posttransplant , though TMP-SMX may also have a role in preventing some community-acquired respiratory respiratory community-acquired some preventing in arole have may also TMP-SMX , though Practice recommendations regarding prophyla regarding recommendations Practice Dapsone is often used as a second-line agent for PJP prophylaxis. Some reports of daily daily of reports Some prophylaxis. PJP for agent second-line a as used often is Dapsone In general, anti- In general, 51,55,56 Pneumocystis . Agents for prophylaxis Table used areoutlined5. in a, severe nephritis or hepatiti or nephritis a, severe prophylaxis is recommended for all solid organ transplant transplant organ solid all for recommended is prophylaxis r patients receivingr patients imm perceived overall risk and intensity of of intensity and risk overall perceived 2 . In any transplant population, the risk is considered considered is risk the population, transplant any In . certain autoimmune diseases), the risk for PJP may may PJP for risk the diseases), autoimmune certain T. gondii T. 51,54,55 cumented severeside effects with TMP-SMX agents should be considered second line agents agents line second considered be should agents e. Other potential effects include hepatitis, hepatitis, include effects potential Other e. xis would include TMP-SMX as the drug of drug the as TMP-SMX include would xis . For lung and small bowel transplant transplant bowel small and lung For .

57 , thus should be used in combination if if combination in used be should , thus unosuppressive drugs or drugs unosuppressive s, or in cases of documented documented of cases in or s, Toxoplasma Accepted Article This by is protectedarticle reserved. Allrights copyright. unrecognized often are effects side are associated with G6PD deficiency, enzyme thou effects of dapsone include hemolytic anemias and defi (G6PD) dehydrogenase glucose-6-phosphate polymerase chain reaction (PCR) techniques techniques (PCR) reaction chain polymerase of infection have been described among renal tr renal among been described have of infection filtering to prevent transmission among infected individuals offacemask use the and PJP with patients immunocompromised of segregation hospital strict recommend to authors events some led have remains These unclear. direct spread person-to-person role of transmission of PJP in the nosocomial setting, theof role environmentalcontamination vs. contro infection regarding recommendations effective prophylaxis should prevent infection; without more data,definitive formal spread remainselusive. reservoir nature experts Some in issues control Infection anddapsone. TMP-SMX like , reported due to resistance reported to due Atovaquone is well-studied in the HIV population and has also been studied in small small in studied been also has and population HIV the in well-studied is Atovaquone prospective trials of adult organsolid transplant recipients at a dose of 1500mg orally once daily be beneficial. Older studies demonstrated demonstrated studies Older comparisonswith community-acquired strains are lacking acquisition; nosocomial for argument the strengthening strains, of numbers limited demonstrate reservoir a as serve could individuals immunocompromised been well-documented in patients taking 1000mg less or daily have infections breakthrough unclear, be may dosing ideal Although noted. rarely are transaminases diarrhea. Rash and gastrointestinal complaints arecommon most the side effects. Increased hepatic susceptible in transport electron mitochondrial inhibiting by acts atovaquone suspension, in only Available 60 Airborne transmission of of transmission Airborne . If so, asymptomatic immunocompetent carriers of carriers immunocompetent asymptomatic so, . If Pneumocystis . Absorption is enhanced by fatty foods and decreased in the setting of of setting the in decreased and foods fatty by enhanced is Absorption . 59 . Atovaquone may also have activity against the bradyzoites of of bradyzoites the against activity have also may Atovaquone . Pneumocystis Pneumocystis Pneumocystis jiroveci 58 . Thus, periodic screening including complete bloodcount may in air samples fromhospital patient roomscare using 62,63 l in the l inhospital the cannot be made. ansplant recipients at individual care centers care centers individual at recipients ansplant . Molecular genotyping studies in outbreaks outbreaks in studies genotyping . Molecular ciencies.commonly most The associated side have suggested the possibility of person-to-person of person-to-person possibility the suggested have gh G6PD deficiency is not a prerequisite. These These aprerequisite. not is deficiency G6PD gh methemoglobinemia. Classically thesesymptoms islikely based on animal studieswhile a 17,64,65 61 13 Pneumocystis . While uncommon, nosocomial clusters clusters nosocomial uncommon, While . . It should be noted that use of of use that noted be should . It 5,51 . Although these data support the the support data these Although . and a recent failure has been has failure recent a and or infected infected or 10,13,14 51 . . Accepted Article This by is protectedarticle reserved. Allrights copyright. • • • • elucidated and may provide new targets for prophylaxis and therapy therapy and prophylaxis for new targets may provide and elucidated Acknowledgement: This manuscript was modified from the Guideline included in the 3 the in included Guideline the from modified was manuscript This Acknowledgement: Transplantation. of Society American the by endorsed and 4): 272-279 (Suppl 2013;13 Transplantation of Journal American the in published JA Fishman and Martin SI by written Guidelines Diseases Infectious AST the regions geographic various in and outbreaks in analysis genome by advanced havebeen which studies for The environmental reservoir Future Directions and Research only in the early phases of development only of early phases in the currently are which vaccines effective provide to and populations risk high defining further in assist Enhanced understandefforts to theimmune response toPneumocystis warranted are andwill likely assays for invasive disease arerequired to advance prevention and epidemiologic investigations. are needed especially in light severalof reports of late on-set disease potential the and periods risk high defining better

Outbreaks of of Outbreaks high). (strong, PJP of prophylaxis for choice of drug the is (TMP-SMX) Trimethoprim-sulfamethoxazole indicated (strong, low). chroni or infection PJP prior of history with or immunosuppression, of intensity higher with recipients, transplant bowel small and lung For least 3-5% of PJP among transplant recipients (strong, moderate). at of incidence an with programs andfor moderate) (strong, posttransplant months 6-12 least Anti- spread. spread. 9,66-69 Pneumocystis . The mechanisms underlying adaptation of the organism to various hosts remain to be be to remain hosts various to organism of the adaptation underlying mechanisms . The Pneumocystis prophylaxis is recommended for all solid organ transplant recipients for at forat recipients transplant organ solid all for recommended is prophylaxis may occur in nosocomial settings, possibly due to person-to-person person-to-person dueto possibly settings, nosocomial in occur may Pneumocystis 73 . . remains unknown. This has hindered epidemiologic epidemiologic hindered has This unknown. remains c CMV infections, prolonged prophylaxis may be may prophylaxis prolonged c infections, CMV need for prolonged or rein or prolonged for need 9,70-72 22 . New, more rapid diagnostic diagnostic rapid more . New, . In addition, studies studies addition, . In stitution of prophylaxis prophylaxis of stitution rd Edition of of Edition Accepted Article This by is protectedarticle reserved. Allrights copyright. of evidence Molecular PM. B, Hauser A,Tonshoff Nahimana C, Wendt B, Hocker Pneumocystis transmission in pediatric transplant unit. Emerg InfectDis 2005;11:330-2. 14. 71. Pneumocystis nosocomial of evidence Molecular al. T, et Wendler R, Schuhegger S, Schmoldt jirovecii transmission among 16patients after kidn 13. Kovacs JA, Gill VJ, Meshnick S,Masur H.New insightsinto transmission, diagnosis, anddrug treatment of Pneumocystis cariniipneumonia. Jama 2001;286:2450-60. 12. 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Trials N Engl 1998;339:1889-95.Med J Pr Community both. or sulfonamides, trimethoprim, tolerate cannot who infection HIV with patients in pneumonia the carinii for dapsone with Pneumocystis compared of prevention Atovaquone al. et TM, Yurik RL, Murphy WM, El-Sadr 106. pneumonia: review. Clina Infect 1998;27:191-204. Dis Hughes in preven WT. of dapsone the Use 105. Care Med 1995;151:1233-8. Granulocyte- JE. Shellito RC, Beckerman WR, Summer S, macrophage Nelson NB, colony D'Souza JF, stimulating Mandujano factor and Pneumocyst 104. organ transplant recipients. Transplantation 2007;84:685-8. addition totrimethoprim-sulfamethoxazole treatmentsevere pneumocystis for pneumonia Utili solid in R,Durante-Mangoni E, Basilico Mattei A, Ragone C, Grossi E, EfficacyP. caspofungin of 103. Infect 2006;25:52-4. Dis Pneumocystis pneumoniaduring conditioning for bone marrow Annaloro transplantation.Della C, VolpeUsardi JClin Eur A, MicrobiolLambertenghi P, Deliliers G. Caspofungin treatment of 102. 1998;42:1985-9. Chemother Agents Antimicrob carinii. Pneumocystis of models murine in pneumocandin, PowlesLiberator MA, P, Anderson J,etal. EfficacyMK-991 of (L-743,872), a semisynthetic 101. Sciences the Unitedof ofStates America 1990;87:5950-4. 1,3-beta-glucan with pneumonia Schmatz DM, RomancheckMA, Pittarelli LA, al. Treatmentet ofPneumocystis carinii 100. Fishman JA. Treatment of infectiondue toPneumocystis carinii. Antimicrob Agents Chemother 1998;42:1309-14. 99. four of evaluation pneumonia: Pneumocystis of Diagnosis al. et R, Badura SS, Cale F, Esteves serologic biomarkers.Microbiol Clin Infect 2015;21:379 e1-10. 98. synthesis inhibitors.Proceedings of Nationalthe Academy of of low-dose atovaquone prophylaxis against against prophylaxis atovaquone low-dose of tion of and treatment Pneumocystiscarinii n/primaquine as prophylaxis for Pneumocystis Pneumocystis for prophylaxis as n/primaquine ogram for Clinical Research on AIDS and the the and on AIDS Research Clinical for ogram is carinii pneumoniamice. AmJRespirin Crit Accepted Article Other clinical factors factors clinical Other therapies Immunosuppressive Mycophenolate mofetil mofetil Mycophenolate This by is protectedarticle reserved. Allrights copyright. Table 1. Calcineurin inhibitors Antibody therapies Allograft rejection Corticosteroids Chemotherapy Chemotherapy CMV disease Risk Factor Comments Comments Factor Risk Sirolimus Risk Factors for theDevelopmentof uncontrolled human data, leading to theories about it being protective protective being it about theories to leading data, human uncontrolled azathioprinerenal transplantation in to compared A cyclosporine with risk greater suggest data Limited PJP PJP for factor risk anindependent is CMV of effects immunosuppressive Systemic PJP has been related to the degree and intensity of immunosuppression in in immunosuppression of intensity and degree the to related been has PJP Mycophenolate may have anti- have may Mycophenolate highest risk of PJP being in the 1 to 6 month posttransplant time period period time posttransplant month 6 to 1 the in being PJP of risk highest Antilymphocyte antibodies for graft rejectionor in induction are linked to the intensity and duration of neutropenia neutropenia of duration and intensity to related infection for Risk bleomycin. and fluorouracil, methotrexate, including agents chemotherapeutic numerous with reported PJP prednisone for 12 weeks weeks 12 for prednisone of mg/day 30 to equivalent one series in therapy of duration and dose 90%. median identified in to common corticosteroids up feature The as a Retrospective case series on patients have non-HIV-infected with PJP may be confused PJP with may beconfused that pneumonitis interstitial of syndrome aclinical with associated Sirolimus for PJP factors risk areindependent cytarabine anti-metabolite the and cladribine, Alemtuzumab may confer the highest risk for PJP of antibody therapies therapies antibody of PJP for risk highest the confer may Alemtuzumab regimens compared to cyclosporine A cyclosporine to compared regimens tacrolimus-based on recipients transplant renal among PJP of incidence definitive data are lacking. lacking. are data definitive 51 ; CMV and PJP coinfectionwell-reported 74,75 . Pneumocystis 24,25 81 . . Pneumocystis pneumonia pneumonia 80 3 5 . Retrospective study with higher higher with study Retrospective . . . Purine analogs, fludarabine and and fludarabine analogs, . Purine effects in animal models and and models animal in effects 23,82,83 . 78 77 76 , . . 79 ; Accepted Article Low CD4+ T cell counts counts cell T CD4+ Low This by is protectedarticle reserved. Allrights copyright. HIV=Human immunodeficiency virus, PJP= virus, immunodeficiency HIV=Human Neutropenia Neutropenia GVHD GVHD HSCT=Hematopoietic stemcell transplant,GVHD=Graft host vs. disease GVHD GVHD when stillbeing maintained on immunosuppressant therapies for ongoing PJP develop to likely more are HSCT from out months 6 than greater Patients counts to<200cells/mL,or <20% of the totalcirculating lymphocytes directly is linked tothe fall cell of CD4+T In HIV infection, risk the for PJP 500 ×10 counts of <200cells/ml and associated with absolutelymphocyte count < episodes ofrejection acute transplant recipients development of PJP in transplant recipients recipients transplant in PJP of development the for factor risk potential a as been suggested has neutropenia Prolonged factor PJP for in recipientsHSCT chemotherapy chemotherapy cell T 4+ CD with patients in occurred recipients SOT in diagnosis of PJP or exogenous immunosuppression Lowcounts cell CD4+ T may reflect other processes such ascoinfection viral 84 . 6 cells 86,87 89 , and autoimmune disease and hematological malignancy hematological and disease autoimmune and , . Lymphopenia and decreased CD4+T cell counts is a risk arisk is counts cell CD4+T decreased and . Lymphopenia 3 Pneumocystis , and directly linked to treatment for and number of of number and for treatment to linked directly , and 83 . 88 ,solidreceiving patients tumor 23,51 pneumonia, CMV=Cytomegalovirus, CMV=Cytomegalovirus, pneumonia, . 51 . 85 . 73% 90 . Accepted Article This by is protectedarticle reserved. Allrights copyright. 23-24% 92-96% Hypoxemia 78-91% 30-34% Abnormal radiography chest Abnormal lung auscultation on exam Chest pain Incidence Cough 71-81% Dyspnea 66-68% Fever 81-87% Sign or Symptom PJP of Table 2. Signs and Symptoms of Symptoms of and Signs Pneumocystis pneumonia pneumonia Accepted Article This by is protectedarticle reserved. Allrights copyright. β (LDH) Lactic dehydrogenase Serum stains calcofluor or polychrome, Silver, testing acid nucleic PCR, quantitative Real-time assays Immunofluorescence technique Diagnostic specimens Other Respiratory Moderate Sputum Induced Strong (VATS) thorocoscopy assisted pathology lung other BAL, of yield Increases video- or biopsy Open Lung biopsy Transbronchial Lavage Bronchoalveolar specimen Diagnostic -D-glucan -D-glucan SPECIMEN/TECHNIQUE RECOMMENDED SPECIMEN/TECHNIQUE USAGE a

Table 3. malignancies, stem transplantcell and solid organ transplant recipients* Recommended diagnostic approachpatients toPJP in with hematological infection from carriage carriage from infection in BAL;Quantification cannot distinguish stains over other yield increased method; diagnostic microscopic sensitive Most specimenAlternative yield > toBAL, required not generally diagnosis, for standard Gold > yield Allows detection of multiple etiologies; tool; tool; diagnostic adjunctive as useful specific, Not High Not specific, generallypositive PJP in Strong Exclusion of PJP by negative BAL only burden Not a good alternative, low organism

94,95

β -D-Glucan is component of component is -D-Glucan 80% 96 92,93 . 43,91

94

40,46,97

P. P. 50% 98 Weak Low RECOMMENDATION RECOMMENDATION STRENGTH OF Strong High Strong Low Strong High Strong Low Strong High Strong Low Weak Moderate QUALITY OF EVIDENCE Accepted Article This by is protectedarticle reserved. Allrights copyright. Low *PJP diagnosis should not rely solely on clinical criteria or imaging. Strong a mutations synthase Dihydropteroate outbreaks suspected of Investigation sequencing Genotyping, Includes sputa and upper respiratory samples (nasopharyngeal aspirates, nasal or oral washes). washes). or oral nasal aspirates, (nasopharyngeal samples respiratory upper and sputa Includes o eomne ek Low Weak Not recommended jiroveci cell wall cell 40,98

Pentamidine Pentamidine sulfamethoxazole (TMP-SMX) Trimethoprim- Primaquine and clindamycin clindamycin and Primaquine Atovaquone Accepted Article Comments Dosing Agents This by is protectedarticle reserved. Allrights copyright. Table 4. Therapeutic options for optionsTherapeutic for treating combination withclindamycin 600-900 Primaquine 15-30 mg po qd in doses. daily 2 into divided or daily orally, mg), 4 -24 mo: 45mg/kg (maximum 1500 doses. daily 2 into or divided (max mg), 1500 orally, daily 1 -3 mo and 24 mo-12 y: 30–40 mg/kg Children: used) commonlybidmg (higher 1500 doses to bid po mg 750 Adults/Adolescents: needed if mg/kg/day 2-3 to reduction dose All ages: 4mg/kg/day IV initially with tid po given be can tablets double-strength milder two disease, be sufficient. In doses every 6-8 hours; lowerdoses may divided IV in given TMP component the Adults/Adolescents:15-20 mg/kg/dayof tid-qid tid-qid po be given can dosing daily same the disease milder In hours. 6 every given IV component SMX the of mg/kg/dose the TMP component and 19to 25 Children: 3.75-5mo >2 mg/kg/doseof Pneumocystis pneumonia pneumonia mild tomoderate PJP infections inAIDS. This combination testedpatients in with (strong recommendation, low evidence). infection. tested only inmild andPJP moderate and absorption oral variable with only Atovaquone availableoral in suspension evidence). (strong recommendation,moderate transplant. pancreas of setting in Avoid disturbances. electrolyte and failure renal suppression, marrow bone hyperglycemia, include pancreatitis, hypoglycemia, after cessation ofside therapy; effects effects side of amelioration complicate may half-life prolonged daily; once period hour 1-2 over given Infusions evidence). (strong recommendation,moderate corticosteroids (below). adjunctive consider May hydration. maintain and renalfunction Correct for mostPJP. effective for systemic therapy remainsthe TMP-SMX drug of choice; choice; of drug Caspofungin and TMP-SMX TMP-SMX and Caspofungin Macrolide SMX and recommend) to children (not studied adequately in sulfadiazine and Pyrimethamine recommend) to children (not studied adequately in trimethoprim and Dapsone recommend) to children (not studied adequately in ( Trimetrexate with folinic acid Acceptedno longer available Article This by is protectedarticle reserved. Allrights copyright. ) mg IV or po q6-8 hours hours q6-8 po or mg IV Trimetrexate 45 45 mg/mTrimetrexate dysfunction) hepatic severe reduced the setting in to of moderate combination with TMP-SMX (dose 50 mg/m2 (max: mg/dose)50 IV qd in by followed 70mg/dose); day (max: 1 mg/m2 3mo-17y: IV qd: mg/m2on 70 Children:caspofungin: 0-<3mo 25 : dysfunction) setting of hepatic to moderate severe with TMP-SMX (dose reduced in the combination in after qd IV mg by 50 followed 1, day on caspofungin of dose Adults/Adolescents: IVloading mg 70 vivo sulfamethoxazole may be synergistic in azithromycin in combination with Macrolides suchclarithromycin as or doses in divided combination with sulfadiazine po 4g qd followed by mg 50-100 qd po in Pyrimethamineof load mg 100-200 po, tid divided po mg/kg/day combination with trimethoprim 15 Dapsonepo 100mg qd used in with TMP 5 mg/kg /day/dose potid /day/dose mg/kg 5 with TMP qd po mg/kg/dose 2 dapsone: Children: (80 mg/m acid 20 mg/m 20 acid concomitantlywithadministered folinic kg) <50 patients in IV mg/kg/day 99

2 total daily); Folinic acid 2 po or IV every 6 hours hours every 6 IV or po 2 /day IV (or /day1.5 IV (or

SMX. inferior outcomes compared toTMP- supplementation; acid folinic without suppression bonemarrow Severe toxicity. reduce to qd po 10mg acid folinic with supplement available; data Limited evidence). (strong recommendation,moderate setting ofG6PD deficiency. the in beavoided should Primaquine increase infection by can clindamycin of use Long-term Pneumocystis against activity have Echinocandins (weak recommendation, low evidence). (weak recommendation, low evidence). (weak recommendation, low evidence). intolerant.G-6-PD Checkdeficiency. sulfa in reactions allergic may elicit patients with sulfa allergies; dapsone some in used been has Combination (weak recommendation, low evidence). (weak recommendation, low evidence). dataFew supportto combination. this marrow transplantation SMX for PJP in solid organand bone Case reports in combination with TMP- (weak recommendation, low evidence). (weak recommendation, low evidence). unknown. efficacycompared toTMP-SMX in animal models models animal in Clostridium difficile Clostridium 102,103 . Clinical 100,101 . . Accepted Article dosing Standard factors Colony-stimulating Corticosteroids agentsAdjunctive This by is protectedarticle reserved. Allrights copyright. day a times qid=four aday; times three CSF=Granulocyte/macrophage colony stimulating fact GM- dehydrogenase, G6PD=Glucose-6-phosphate syndrome, immunodeficiency PJP= TMP-SMX=Trimethoprim-sulfamethoxazole,

0.5mg/kg po qd for 10 days days 10 for qd po 0.5mg/kg then days, 5 for bid po 0.5mg/kg then days, 5 for bid po 1mg/kg Children: weeks 1-2 of period tid a 5-7 over after with taper days bid- po/iv equivalent) (or of prednisone mg mg-60 40 Adults: and Adolescents days beyond cessation of trimetrexate trimetrexate of cessation days beyond therapy 3 shouldat least extend for Pneumocystis or, po=orally, qd=daily, bid= twice a day, tid= pneumonia, AIDS=Acquired AIDS=Acquired pneumonia, success tried in animal modelsPJP of with some been has anadjuvant as GM-CSF of Use in the setting of hypoxia (pAO withinof 72hourspresentation patient Corticosteroids best administered are are available. available. are (strong recommendation, low evidence). 70mmHg). 104 . clinical No datain humans 2 < Agents Dosing Comments Comments Dosing Agents cotrimoxazole) cotrimoxazole) (TMP-SMX, sulfamethoxazole Trimethoprim- Clindamycin and Up to 300 mg of clindamycin po po clindamycin of mg 300 Up to Accepted and Clindamycin Pentamidine Atovaquone Dapsone Article This by is protectedarticle reserved. Allrights copyright. Table 5. Specific prophylactic agents prevention for of qd with 15 mg of pyrimethamine with pyrimethamine 15mgof qd 4 weeks q3- nebulizer aerosolized through All mg ages: 300 administered mg),1500 orally, daily mo:4 -24 45mg/kg (maximum mg/kg mg), (max 1500 orally, daily 1 -3 mo and 24mo-12 y:30–40 Children: daily Adults/Adolescentsorally, 1500 qd po mg 50-100 Adults/Adolescents weeklyoreither daily threetimes strength) po (double strength) TMP/800 (double mg SMX mg (singlestrength) or160 mgSMX mg TMP/400 80 either as given be Can Adults/Adolescents: 200 200 mg), orally, week every (max mg/kg 4 or daily once orally, Children:mg/kg 2 (max 100mg), twice or three times weekly daily twice given and divided dose daily or week a days 7 daily once andTMP givenmg 1600 SMX) 50 mg/kg orally320 (max dose mg 25– sulfamethoxazole, and mg/kg Children: trimethoprim, 5–10 Pneumocystis though clearly less effective than TMP-SMX or TMP-SMX clearlythoughthan less effective Prophylaxis somewhat efficacious inAIDS patients, (strong recommendation, moderate evidence). anddapsone. TMP-SMX to compared infection breakthrough of incidence Higher bronchospasm. and cough include effects Side µ. 1-3 droplets for nebulizer with personnel experienced requires administration pentamidine Aerosolized PJP preventing in dapsone to equal was atovaquone In HIV patients intolerant of TMP-SMX, prophylaxis prophylaxis remains TMP-SMX the HIV-infected patients patients HIV-infected Dapsone is a second-line agent forprophylaxis in doses of 1000mg ordaily less (strong recommendation, moderate evidence). (strong recommendation, highevidence). tolerated effects of dapsone underappreciated in SOT in underappreciated dapsone of effects (weak recommendation, low evidence). 106 . Data in SOT recipients show it well- it show recipients SOT in . Data 51

. Failures of atovaquone reported at at . Failures reported of atovaquone 57 . 105 drug of choice of drug . The hematologic side side hematologic . The 51,107 . for PJP 58 . Accepted Article recommend) to children in adequately studied (not pyrimethamine This by is protectedarticle reserved. Allrights copyright. administered3 times thisregimen have clinicians (some po qd weekly instead of daily) dapsone comparitors comparitors dapsone (weak recommendation, low evidence). intolerance maybelimiting. than for aerosolized pentamidine. Gastrointestinal 108 . Failure rate also. rate higher Failure