Consensus Guidelines for Diagnosis, Prophylaxis and Management of Pneumocystis Jirovecii Pneumonia in Patients with Haematological and Solid Malignancies, 2014 L

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Internal Medicine Journal 44 (2014)

Consensus guidelines for diagnosis, prophylaxis and management of Pneumocystis jirovecii pneumonia in patients with haematological and solid malignancies, 2014 L. Cooley,1 C. Dendle,2,3 J. Wolf,4,5 B. W. Teh,6 S. C. Chen,7,8,9 C. Boutlis10,11 and K. A. Thursky6,12

1Department of Microbiology and Infectious Diseases, Royal Hobart Hospital, Hobart, Tasmania, 2Departments of Infectious Diseases and General Medicine, Monash Medical Centre, Monash Health, Clayton, Victoria, 3Southern Clinical School, Faculty of Medicine, Monash University, Melbourne, Victoria, 4Department of Infectious Diseases, St. Jude Children’s Research Center, Memphis, Tennessee, USA, 5University of Tennessee Health Sciences Center, Memphis, Tennessee, USA, 6Department of Infectious Diseases and Infection Control, Peter MacCallum Cancer Centre, East Melbourne, Victoria, 7Centre for Infectious Diseases and Microbiology Laboratory Services, ICPMR – Pathology West, Westmead, New South Wales, 8Department of Infectious Diseases, Westmead Hospital, Westmead, New South Wales, 9Sydney Medical School, The University of Sydney, Sydney, New South Wales, 10Department of Infectious Diseases, Wollongong Hospital, Wollongong, New South Wales, 11Graduate School of Medicine, University of Wollongong, Wollongong, New South Wales, 12Victorian Infectious Diseases Service, The Doherty Institute for Infection and Immunity, Parkville, Victoria

Key words Abstract Pneumocystis carinii, Pneumocystis jirovecii, haematological malignancy, solid-organ Pneumocystis jirovecii infection (PJP) is a common cause of pneumonia in patients with tumour, prophylaxis, treatment. cancer-related immunosuppression. There are well-deﬁned patients who are at risk of PJP due to the status of their underlying malignancy, treatment-related immunosup- Correspondence pression and/or concomitant use of corticosteroids. Prophylaxis is highly effective and Karin Thursky, Department of Infectious should be given to all patients at moderate to high risk of PJP. Trimethoprim- Diseases, Peter MacCallum Cancer Centre, sulfamethoxazole is the drug of choice for prophylaxis and treatment, although several Locked Bag Number 1 A’Beckett Street, East alternative agents are available. Melbourne, Vic. 8006, Australia. Email: [email protected] doi:10.1111/imj.12599

Introduction disease is generally more severe in these patients, with increased length of hospital stay and higher rates of inten- Pneumocystis jirovecii infection causes pneumonia (PJP; sive care unit (ICU) admission and mechanical ventila- also known as PCP) in patients with immunosuppression tion, compared with HIV-infected patients.1–4 Significantly due to underlying malignancy, organ transplantation or higher mortality rates are also observed in non-HIV- other conditions. The infection is best studied in those infected individuals (34–39%) compared to those with with human immunodeficiency virus (HIV)/acquired HIV (6–7%).1,5,7 immune deficiency syndrome, as there are significant With a focus on HIV-negative populations, this guide- differences in the clinical features of PJP between HIV- line outlines diagnostic approaches and provides recom- 1–5 infected and non-infected individuals. mendations for prophylaxis and treatment of PJP in Infection in immunosuppressed HIV-negative individ- adults and children undergoing chemotherapy for uals has a shorter duration of onset and fewer systemic haematological and solid-organ tumours. It does not 1 symptoms than in HIV-infected individuals. Bron- discuss P. jirovecii affecting extra-pulmonary sites or infec- choalveolar lavage fluid from immunosuppressed non- tion in the setting of organ transplantation. HIV-infected patients shows lower concentrations of organisms but higher inflammatory scores.6 Clinical Methodology Conflicts of interest: The following authors are consultants or advisory committee members or receive honoraria, fees for Questions asked service, or travel assistance from, or have research or other associations with the organisations listed: Sharon Chen – Gilead, In preparing this update, we aimed to address the follow- Merck Sharp & Dohme, Pfizer; Karin Thursky – Pfizer. ing questions:

1 What are the current diagnostic strategies for PJP? cation, including: major surface glycoprotein (MSG) 2 Which patients with haematological and solid malig- gene, mitochondrial large subunit (mtLSU) rRNA gene, nancies are at risk for PJP? dihydropteroate synthase (DHPS) gene, dihydrofolate 3 What is the evidence for prophylaxis? Which agents reductase (DHFR) gene, heat shock protein (HSP)70 are most effective? gene and the beta-tubulin gene. Multicopy genes such 4 What are the first- and second-line agents for treat- as mtLSU and MSG offer the greatest sensitivity for ment of PJP? P. jirovecii detection.10 However, they lack specificity 5 Is there any evidence to keep patients with confirmed and have a low positive predictive value due to the PJP in clinical isolation? increased detection of P. jirovecii in patients who are colonised but otherwise well. With a high negative predictive value, PCR is best utilised for excluding the Search strategy diagnosis of PJP.12 A literature review was performed using PubMed to Quantitative PCR (qPCR), with defined upper- and identify papers published since 2007 that pertained to PJP lower-quantitation thresholds of P. jirovecii copy in patients with haematological and solid tumours. number, can be used to distinguish true infection from Search terms included (in combination) ‘Pneumocystis colonisation.13–18 However, there remains an indetermi- carinii’, ‘Pneumocystis jirovecii’, ‘immunocompromised’, nate zone of unclear clinical significance.14–17 Further, ‘non-HIV’, ‘treatment’, ‘prophylaxis’ and ‘diagnostics’. these quantitation thresholds will vary between different patient populations; clinicians should be cautious Diagnosis of PJP of relying on them as a measure to guide diagnosis or therapy. To improve accuracy, combined diagnostic algorithms have been proposed. These use qPCR and Microbiological tests β(1,3)-D-glucan on serum testing to classify patients Due to difficulties with isolating and culturing this into infection and colonisation categories,19 but valida- pathogen, microscopic examination of respiratory speci- tion is still required in patients with malignancy. mens using various staining methods is used to visualise Due to heterogeneity of methods and diversity of and identify the morphological structures of P. jirovecii. chosen qPCR targets in published literature, gener- Methenamine silver and toluidine blue preparat- alisability of reported cut-off values is limited. Each ions stain only the cyst wall and do not allow detect- institution must establish and validate its own qPCR ion of trophozoites. However, Giemsa stains detect cut-off values appropriate to the preferred molecular all life stages of P. jirovecii. Direct and indirect method. While molecular tests may aid clinical diagno- immunofluorescent assays (DFA, IFA) are specific for sis, there is a lack of correlation between qPCR and different life stages, depending on the antibody used. the clinical features or outcomes of PJP.20 Therefore, Comparative studies have shown DFA and IFA to be the clinicians should take an individual’s clinical risk of most sensitive stains for P. jirovecii in sputum and PJP into consideration when interpreting the cycle bronchoalveolar lavage, with sensitivities of 97% and thresholds. 90% respectively.8 These assays are also commercially Studies on the use of molecular diagnosis have largely available. been based on bronchoalveolar lavage sampling.15,16 Overall, the accuracy of staining methods is highly Although induced sputum samples have also been evalu- dependent on the quality of respiratory specimen, sample ated, they can be demanding to perform on wards and in processing, reaction of the specimen to the stain chosen children.17 Others have reported the use of oral washes and experience of the laboratory observer. The lower and expectorated sputum, but the clinical validity of burden of P. jirovecii in non-HIV-immunocompromised these approaches requires further evaluation.20,21 These patients, and the likelihood that they may already be on approaches certainly produce a lower yield – that may be anti-pneumocystis prophylaxis, remains a challenge for useful – but, overall, their value in this particular setting diagnosis.9 remains unclear. Staining methods have now largely been supplanted by highly sensitive molecular techniques, using semi- or Radiological findings fully quantitative polymerase chain reaction (PCR) tar- geting P. jirovecii-specific genes.10 A meta-analysis of PCR Imaging studies are an essential companion to microbio- studies has shown a pooled sensitivity of 99% and speci- logical testing for diagnosing PJP. High-resolution com- ficity of 92% in the non-HIV patient population.11 puted tomography (CT) is the most commonly used and A variety of gene targets can be used for PCR amplifi- reliable radiological modality for detecting pneumonic

© 2014 The Authors Internal Medicine Journal © 2014 Royal Australasian College of Physicians 1351 Cooley et al. changes in immunocompromised patients.22 The most Table 1 Patients with malignancy at high risk for Pneumocystis jirovecii frequent CT findings are bilateral, ground-glass changes pneumonia 22 with apical predominance and peripheral sparing. In • Heavily pre-treated patients (e.g. multiple lines of chemotherapy for non-HIV-immunocompromised patients with PJP, signs of Hodgkin and non-Hodgkin lymphoma, lymphoproliferative diseases or consolidation are detected more frequently on CT – and myeloma). cystic changes less frequently – than in HIV-positive • Relapsed disease. patients with PJP.23,24 The range of other radiological fea- • High-dose corticosteroids (often in combination with chemotherapy). • Chemotherapy, monoclonal antibodies or diseases causing prolonged tures seen in PJP include a combination of ground glass lymphopenia (e.g. ALL, alemtuzumab, R-CHOP14). and consolidative opacities, cystic changes, linear- reticular opacities, solitary or multiple nodules and paren- chymal cavities.25 With treatment, the vast majority of these changes resolve.22 PJP risk in patients with Nuclear imaging modalities such as 18F- haematological malignancy fludeoxyglucose-positron emission tomography (FDG- PET) have been used as an adjunct to plain X-ray or CT.26 Specific patient groups with underlying haematological The FDG-PET findings correlate well with conventional malignancy have been identified to be at high risk of imaging, showing bilateral uptake of FDG in the upper PJP.31 These findings have been used to inform guidelines zones of the lungs.27 Abnormalities on PET scans, leading regarding institution of PJP prophylaxis. However, there to PJP diagnosis in the setting of normal chest radio- have been important shifts in the treatment of graphs, have been reported, which suggests a potential haematological malignancies30,32 and diagnostic algo- role for PET scans in facilitating early diagnosis. However, rithms since the publication of earlier studies. Further- limited access to FDG-PET is currently a significant more, early evaluation did not encompass emerging barrier to use.28 subgroups of patients with haematological malignancy. The estimated risk of PJP in these groups, such as acute myeloid leukaemia,3,33,34 myelodysplasia, myeloma3,35–37 Determining patient risk and the need 38–46 for PJP prophylaxis and lymphoma, are based on case reports and are incompletely defined. Antimicrobial prophylaxis is highly successful in pre- The most easily quantifiable risk factors in pat- venting PJP in patients with immunosuppression from a ients with haematological malignancy are choice, dose diverse range of causes, including solid-organ transplan- and combination of chemotherapy agents. Other tation and malignancy. Chemoprophylaxis was first factors, such as age, comorbidities, type47 and stage of demonstrated to be highly effective in preventing PJP in malignancy, surgery, radiation and immune param- a randomised controlled study of paediatric oncology eters,45 also contribute to risk but are more difficult to patients.29 Pooled data from 11 clinical trials showed a quantify. reduction in the relative risk (RR) of PJP (0.09, 95% Patients at highest risk of PJP are those undergoing confidence interval (CI) 0.02–0.32) in patients receiving treatment for acute lymphoblastic leukaemia (ALL) (up trimethoprim-sulfamethoxazole (TMP-SMX) prophy- to 16%)48 and for allogeneic haemapoietic stem cell laxis compared with patients receiving no intervention, transplant (HSCT) (from 0.3% to 15%).3,49,50 In these placebo or an antibiotic without PJP activity.30 TMP- populations, the number needed to treat has been esti- SMX prophylaxis has been shown to have a mortality mated to be 11.30 benefit and its use is recommended in settings where Patients receiving prolonged, high-dose corticosteroid the risk of PJP is estimated to exceed 3.5% (grade A treatment (16–25 mg of prednisolone per day or ≥4mg recommendation).30 Prophylaxis is routinely used in dexamethasone daily for ≥4 weeks) are also at high risk children for a wider range of malignancies, including of PJP, regardless of underlying type or stage of malig- those with a lower risk of PJP, as TMP-SMX is very well nancy, or use of other chemotherapy agents.51 Certain tolerated. T-cell-depleting agents (e.g. alemtuzumab) will also place In patients with haematological malignancy, both host patients at a higher risk of PJP, particularly if salvage and disease factors, as well as chemotherapy regimens treatment is being administered.52 Further, patients who need to be considered when determining an individual’s have had PJP previously remain at high risk of a subse- risk of PJP (see Table 1). A patient’s risk of PJP is influ- quent episode if their underlying immune deficit persists. enced by multiple factors at any given point in time Patients in whom the risk of PJP is not conclusively and risk should be continually assessed throughout the established, but is likely to be moderate, include those treatment period. with autologous bone marrow transplant,3 and patients

© 2014 The Authors 1352 Internal Medicine Journal © 2014 Royal Australasian College of Physicians Guidelines for prevention and treatment of PJP with haematological malignancy undergoing certain patients, depending on density of dosing.67,68 In a phase 2 high-intensity chemotherapy regimens. In the latter case, trial, 79% of patients developed grade 3–4 lymphopenia, clinicians should be particularly vigilant of R-CHOP14 with two of the first 15 patients (13%) developing PJP.69 (rituximab, cyclophosphamide, adriamycin, vincristine, Subsequent cases have led to a black-box warning rec- prednisolone chemotherapy on a 14-day cycle),38,40,42,43,53 ommending that PJP prophylaxis accompany the use of FCR (fludarabine, cyclophosphamide, rituximab),27 this agent.7,59,70 AVBD (adriamycin, vincristine, bleomycin, dexametha- Collectively, these data suggest that PJP prophylaxis sone),54 gemcitabine55 and high-dose methotrexate. should be considered in solid-tumour patients undergo- Patients with prolonged CD4 lymphopenia, before or ing chemotherapy regimens containing 16–25 mg pred- after initiation of chemotherapy, are also likely to be at nisolone or ≥4 mg dexamethasone daily for ≥4 weeks, as moderate risk of PJP. However, with limited evidence to well as patients undergoing intensive treatment for cer- assess PJP risk in this group, debate still surrounds the use ebral malignancy (grade C recommendation). Prophy- of prophylaxis in this population.56,57 laxis should be continued for 6 weeks after the steroid- Patients with haematological malignancy at lower risk tapering period. A summary of agents for PJP prophylaxis of PJP include those receiving low-intensity chemo- and their indications for use are provided in Table 2. therapy regimens (such as R-CHOP given on a 21-day cycle), provided they do not have other risk Chemoprophylaxis for PJP factors.38,45,46,58 TMP-SMX PJP risk in patients with TMP-SMX is the first-line prophylactic agent for PJP pre- solid-organ malignancy vention in adults and children, and the only agent dem- PJP has been reported to occur in patients undergoing onstrated to be more effective than placebo in prospective chemotherapy for a broad range of solid-organ malignan- randomised trials (grade A recommendation).29,30 Further, cies, including breast, pulmonary, renal, genitourinary limited evidence suggests that TMP-SMX is superior to and colorectal cancer; central nervous system tumours; other agents, especially in younger patients (<2 years of rhabdomyosarcoma and melanoma.4,7,59–61 Despite this, age) and in patients undergoing HSCT (grade D recom- there are no clinical efficacy data supporting the routine mendation).71 The use of TMP-SMX may also confer some use of PJP prophylaxis in these patient groups. protection against other infections in the high-risk patient The inclusion of corticosteroid therapy in the chemo- such as toxoplasmosis, nocardia and bacterial sepsis. A therapy regimen has been consistently reported as a risk systematic review in the HIV population also found that factor for developing PJP in adult patients with solid- the use of TMP-SMX confers some protection against the organ tumours.7,61–63 Adult patients who are receiving development of resistance to other antibiotics.72 high-dose corticosteroid therapy (16–25 mg prednisolone The optimal dose schedule for TMP-SMX is not clear or ≥4 mg dexamethasone daily for ≥4 weeks) appear to due to the limited number of studies comparing regimens be at greatest risk, both during high-dose therapy and the in patients with malignancy or undergoing stem cell steroid-tapering period.59 Patients receiving these kinds transplantation.29,30,73 Once- or twice-weekly prophylaxis of doses are typically undergoing dose-intensive chemo- or 3 non-consecutive days per week may be of equal therapy for lung, breast or brain cancer. There is a paucity efficacy, based on retrospective and observational studies of data in the paediatrics setting, although a dosage (level III-2 evidence).74 Hughes et al. reported that daily equivalent to ≥2 mg/kg per day of prednisone or equiva- and thrice-weekly dosing in children with ALL was lent to a total of ≥20 mg/day for children who weigh equally efficacious.75 Studies in HSCT patients have more than 10 kg, particularly when given for more than reported PJP rates of <1% using doses as low as two 14 days, is considered to be T-cell immunosuppressive.64 single strength (SS) tablets twice weekly, two double Patients with brain tumours are at particular risk of strength (DS) tablets twice weekly and two DS tablets PJP. While the incidence of PJP is low (1.7%) among thrice weekly.76–78 In the absence of clear evidence to patients receiving corticosteroids for brain tumours,65 support various dosing regimens, these guidelines cranial irradiation increases the risk of PJP. Over a support the use of once-daily dosing in adults with SS or 12-month period, PJP has a reported incidence of 6.2% DS or thrice-weekly dosing with DS (grade B recommen- in this population, with a median time to onset of 10 dation). In children, various regimens are acceptable, weeks.66 Temozolomide, an alkylating agent used for the although three days per week is preferred practice. treatment of glioblastoma multiforme, results in signifi- Limitations in TMP-SMX prophylaxis include docu- cant lymphopenia (<500 cells/uL) in 24–100% of mented hypersensitivity, renal impairment, drug

Table 2 Indications for Pneumocystis jirovecii chemoprophylaxis in patients (adults and children) with malignancy and recommended agent

Haematological malignancy (grade of recommendation) Note: Patients may have multiple or cumulative risk factors; consider underlying disease, disease status and treatment-related immunosuppression. Known indications: • Allogeneic HSCT (all) (C) • ALL (all) (A) • AML or lymphoma regardless of treatment protocol (children only) (C) • Autologous HSCT (all children and selected high-risk adults) (C) • Regimens: R-CHOP14, high-dose methotrexate (C) • Lymphocyte-depleting agents (e.g. alemtuzumab) or patients whose CD4 count <200 cells/uL before commencing chemotherapy (C) • Corticosteroids: where 16–25 mg prednisolone or ≥4 mg dexamethasone for ≥4 weeks is planned (C) • Regimens: FCR, ABVD, gemcitabine (single centre reports of higher risk for these regimens; consider prophylaxis) (D)

Solid tumours (grade of recommendation) Regimens where 16–25 mg prednisolone or ≥4 mg dexamethasone for ≥4 weeks is planned (C) Brain tumours, particularly if temozolomide or craniospinal irradiation is planned (B) Other solid tumours undergoing myelosuppressive chemotherapy (children only) (C)

First-line prophylactic agent should be trimethoprim-sulfamethoxazole, unless: (i) Previous allergy or hypersensitivity to sulfa-drugs Recommend: trimethoprim-sulfamethoxazole desensitisation (unless previous anaphylaxis) (ii) Planned methotrexate chemotherapy in adults Recommend: second-line prophylactic agent A second-line prophylactic agent should be used if trimethoprim-sulfamethoxazole is contraindicated: (i) Dapsone, OR (ii) Pentamidine (nebulised, monthly), OR (iii) Atovaquone Prophylaxis should continue for at least 6 weeks after steroid cessation. A longer period of prophylaxis may be required if ongoing chemotherapy (e.g. cytarabine, cyclophosphamide, fludarabine, fluorouracil, methotrexate) is planned. Life-long prophylaxis should be considered if the patient has had a previous episode of PJP and persisting immunosuppression. interactions, myelosuppression and gastrointestinal Mutations in the fas gene of P. jirovecii, which encodes disturbance. The true rate of adverse reactions is the DHPS protein, are associated with prior exposure unknown, but in the adult HSCT population it is estimated to sulphonamides.82,83 When these mutations are pre- to be in the range of 5–15%, and in children it is much sent, reduced susceptibility to TMP-SMX should be lower.77 expected. However, the mutations do not appear to Although one early study suggested increased duration correlate with resistance, as HIV-infected patients with of neutropenia associated with TMP-SMX,79 this study Pneumocystis isolates containing these mutations respond pre-dated current chemotherapy regimens (including use to TMP-SMX therapy.84,85 Helweg-Larsen et al.84 reported of granulocyte colony-stimulating factor). More contem- an association with increased mortality; however, subse- porary studies have not demonstrated an impact upon quent studies have failed to detect such an effect.85,86 degree or duration of neutropenia. It is reasonable to At present, no recommendation can be made with administer TMP-SMX prior to engraftment in children respect to clinical indications or interpretation of receiving HSCT, as there is no evidence of delayed resistance testing. engraftment in this population (level III-2 evidence).80 Oral desensitisation regimens have been used success- Myelosuppression may be exacerbated when TMP-SMX is fully for HIV-infected patients and others with rash, and used in combination with methotrexate, although clinical similar protocols have been used in HSCT patients with a data in adults are conflicting. Concurrent methotrexate success rate of approximately 80%.77 Desensitisation may administration is not a contraindication for use of TMP- be attempted whenever feasible (level II evidence, grade SMX in children receiving treatment for cancer, as there is C recommendation).32 Desensitisation may be considered no evidence for a common, clinically significant adverse for all patients with TMP-SMX-associated rash but is drug interaction in this population (level III-2 evidence).81 contraindicated in those with a prior history of associated TMP-SMX should be used with caution in all patients drug rash with eosinophilia and systemic symptoms with renal and hepatic impairment, and glucose-6- (‘DRESS’), Stevens-Johnson syndrome, or toxic epider- phosphate dehydrogenase deficiency (G6PD). mal necrolysis.

Second-line agents for PJP chemoprophylaxis prevented by the use of inhaled beta-agonists. It should be avoided in patients less than 5 years of age or if there There are no sufficiently powered trials on which to base is a history of asthma. In children, intravenous a recommendation for alternative prophylactic regimens pentamidine is used during the pre-engraftment period in patients with malignancies. Many recommendations in some centres and may be an alternative if no other have been based on studies involving patients with HIV options are available. However, paediatric data are infection. However, these should be interpreted with limited and it should be used with caution if risk factors caution due to possible differences in efficacy and side- for pancreatitis exist.91,92 effect profiles in patients with malignancy. An alternative In one study of patients undergoing HSCT, nebulised agent should be used if TMP-SMX is withheld for any pentamidine had significantly lower treatment-related reason for ≥2 weeks (grade D recommendation). toxicity compared with TMP-SMX (RR 0.19, 95% CI 0.04–0.89).78 Aerosolised pentamidine has the conveni- Dapsone ence of administration at a dose of 300 mg monthly or 150 mg fortnightly. It must be administered through jet- Dapsone is a synthetic sulfone that acts against P. jirovecii nebuliser in a single or negative-pressure room (grade C by inhibiting the synthesis of dihydrofolic acid through recommendation). competition with para-amino-benzoate for the active site Few clinical trials have been undertaken in patients of dihydropteroate synthetase.87 It has 70–80% oral with malignancy. The largest, a retrospective study con- bioavailability with oral dosing achieving high levels of ducted in patients undergoing HSCT, compared concentration in bronchoalveolar lavage fluid.88 Adverse aerosolised pentamidine with TMP-SMX and dapsone. reactions to dapsone include agranulocytosis, aplastic Pentamidine was the least effective, with a higher inci- anaemia, rash, nausea and sulfone syndrome (rash, fever, dence of PJP: 9.1% compared with 0% in patients treated hepatitis, lymphadenopathy and methemoglobinae- with TMP-SMX. Significantly, patients who received mia).89 Dapsone should not be given to patients with pentamidine had increased rates of non-PJP infections G6PD deficiency or to patients who have experienced and a higher mortality 12 months post-transplant com- severe side-effects with TMP-SMX. pared with patients receiving TMP-SMX or dapsone.78 Adverse effects requiring discontinuation of therapy occur in up to 43% of HSCT patients, the most common Atovaquone being rash and haemolytic anaemia. Dapsone is not myelosuppressive.90 Azole antifungal agents elevate Atovaquone is a structural analogue of protozoan dapsone levels so concomitant use should be avoided or ubiquinone. It inhibits the binding of ubiquinone to monitored with caution. cytochrome b, impairing electron-transport mechanisms Dapsone 50 mg BD three times weekly was compared in Pneumocystis mitochondria. It is available as an oral with TMP-SMX DS BD twice weekly in a study of suspension and requires twice-daily dosing. Bioavail- allogenic HSCT patients intolerant of TMP-SMX.77 The ability of the suspension is high and is further augmented incidence of PJP was significantly higher in the dapsone by administration with a fatty meal. The most common group (7.2% vs 0.37%), with a relative risk of 18.8 (95% side-effects include rash, nausea, diarrhoea, elevated CI 4.0–88.6) – although it should be noted that the dose transaminases and headache, which are usually mild. of dapsone used in this study is lower than that currently Colby et al. conducted a prospective randomised trial used in clinical practice (100 mg daily). In a retrospective following adult autologous SCT comparing atovaquone study of HSCT patients, Vasconcelles et al. reported a (n = 20) with TMP-SMX (n = 19) as PJP prophylaxis. No failure rate of 3%.78 cases of PJP were reported in either group, although the treatment-associated adverse event rate was significantly < Pentamidine higher in patients receiving TMP-SMX (40% vs 0%, P 0.003).93 Pentamidine isethionate is an aromatic diamidine deriva- tive available for parenteral or inhalation use. Given the Duration and dosing regimens for high rates of adverse effects associated with parenteral PJP chemoprophylaxis therapy in adults, including pancreatitis, hypoglycaemia (27%) and nephrotoxicity (25%), aerosolisation is the Prophylaxis should continue for a period of time after the preferred mode of delivery for prophylaxis. Nebulised immunosuppressive regimen is ceased. In the setting of pentamidine is usually well tolerated, with the major corticosteroid-containing regimens, prophylaxis should side-effects being coughing and wheezing, which can be be continued while steroids are being weaned and/or for

Table 3 Dosing schedule for Pneumocystis jirovecii chemoprophylaxis in adults and children with malignancy

Adult Children

TMP-SMX 160 + 800 mg (one DS tablet) orally, daily In children >1 month of age: Or 75 mg/m2/dose or 2.5 mg/kg/dose (max 160 mg/dose) orally, 12-hourly, 80 + 400 mg (one SS tablet) orally, daily 3 times a week† Or 160 + 800 mg (one DS tablet) orally, three times a week† Dapsone 100 mg orally, daily In children ≥1 month of age: 2 mg/kg/dose orally, daily OR 4 mg/kg/dose orally, once a week Pentamidine 300 mg inhaled through nebuliser, every 4 weeks Intravenous (≥2 years): (administered through a jet-nebuliser producing 4 mg/kg/dose (max 300 mg) every 4 weeks a droplet size of 1–2 microns) Through inhalation (>5 years): 300 mg inhaled through nebuliser, every 4 weeks (administered through a jet-nebuliser producing a droplet size of 1–2 microns) Atovaquone 1500 mg orally, daily with a high-fat meal 1–3 months: 30 mg/kg/dose orally, daily 4–24 months: 45 mg/kg/dose (max 1500 mg) orally, daily >24 months: 30 mg/kg/dose (max 1500 mg) orally, daily

†Either non-consecutive or consecutive days is acceptable. DS, double strength; SS, single strength. a period of 6 weeks after cessation. With some chemo- SMX. Lower doses (i.e. TMP 15 mg/kg/day and SMX therapy regimens (e.g. alemtuzumab52 and FCR27), where 75 mg/kg/day) have been recommended for mild- there are high rates of late-onset PJP, consideration moderate disease, and as step-down therapy in HIV- should be given to extended PJP prophylaxis for up to 12 infected patients with severe disease following response months, particularly in pre-treated patients. CD4+ moni- to high-dose therapy.97 Intravenous therapy is recom- toring has been advocated as a method to quantify risk of mended for severe disease due to concerns regarding disease development and to guide duration of prophy- drug absorption in critically unwell patients; for mild and laxis in temozolomide and alemtuzumab regimens.52,70 moderate disease, oral or IV therapy may be adminis- However, further studies are required to establish the tered. Based on HIV literature, recommended treatment utility of CD4+ monitoring in the non-HIV patient set- duration is 21 days (grade C recommendation). ting. In patients with ongoing immunosuppression (e.g. graft-vs-host disease), prophylaxis should continue Role of corticosteroids in the treatment of PJP indefinitely. The use of corticosteroids in HIV-associated PJP was Dosing regimens for PJP prophylaxis are provided in established following randomised trials in the late Table 3. 1980s.98–101 Arterial oxygenation at diagnosis was recog- nised as the best prognostic indicator of survival.102 Treatment of PJP Adjunctive corticosteroid therapy commenced at the time of PJP therapy prevented the early decline in oxy- The treatment recommendations for PJP are summarised genation that occurs after initiation of PJP therapy in in Table 4. patients with moderate to severe PJP (arterial-alveolar difference >35 mmHg or an arterial oxygen pressure <70 mmHg). This resulted in a reduction in the likelihood TMP-SMX for the treatment of PJP of respiratory failure and death. Patients with milder In view of its proven clinical efficacy, and the cost and hypoxaemia (arterial oxygen >70 mmHg) may benefit availability of both the IV and oral formulations, TMP- from corticosteroids, but a difference in respiratory SMX is the preferred therapy for mild, moderate and failure and death has not been demonstrated. severe disease for all patients with PJP (grade B Studies in non-HIV-infected patients have produced recommendation).95–97 Initial trials in children using a conflicting results. Retrospective studies3,103,104 showed no dose of TMP 20 mg/kg/day and SMX 100 mg/kg/day benefit in non-HIV-infected patients with moderate to showed an efficacy of 70%, with mortality due to under- severe disease. In contrast, Pareja et al.105 found patients lying immunosuppressive disease. To date, no agent has who received adjunctive steroids required shorter dura- been demonstrated to have outcomes superior to TMP- tion of mechanical ventilation and ICU admission, and

Table 4 Recommended dosing for treatment of Pneumocystis jirovecii infection†

Adult Child Comments

TMP-SMX 5 + 25 mg/kg oral or IV, 8-hourly for 21 >1 month First-line therapy for all levels of severity days Dose as for adult Consider desensitisation except with In severe disease, increase to 6-hourly known history of immediate initially hypersensitivity or TEN/SJS Clindamycin plus 450 mg clindamycin orally, 8-hourly 10 mg/kg (max 450 mg) clindamycin Second-line therapy for severe disease primaquine PLUS orally 8-hourly Test for G6PD deficiency before 15 mg primaquine orally, daily for 21 days PLUS treatment with primaquine In severe disease, increase clindamycin 0.25 mg/kg primaquine (max 15 mg) to 900mg IV, 8-hourly initially then orally, daily for 21 days dose as above. Also, increase primaquine to 30 mg Pentamidine In severe disease where TMP-SMX In severe disease where TMP-SMX Equal second-line therapy for severe contraindicated: contraindicated: disease pentamidine 4 mg/kg (max 300 mg) IV, pentamidine 4 mg/kg (max 300 mg) IV, daily for 21 days daily for 21 days Dapsone plus 100 mg dapsone orally, daily 2 mg/kg dapsone (max 100 mg) orally, Alternative option as first line therapy for trimethoprim PLUS daily mild-moderate disease 5 mg/kg trimethoprim orally, 8-hourly for PLUS There is 20% cross-reaction with 21 days 5 mg/kg trimethoprim orally, 8-hourly for sulfonamides and dapsone; 21 days contraindicated with immediate hypersensitivity or severe reactions. Consider testing for G6PD deficiency prior to use. Atovaquone For mild-moderate diseases: 750 mg <3 months or >24 months: 15–20 mg/kg Third-line therapy orally, 12-hourly for 21 days orally, daily; 3–24 months: 22.5 mg/kg orally, 12-hourly for 21 days

†Refer to Therapeutic Guidelines: antibiotic (version 15) for further details.94 SJS, Stevens Johnson Syndrome; TEN, toxic epidermal necrolysis. reduced supplemental oxygen use. No differences in the from clinical studies involving HIV-infected individuals rates of intubation or in-hospital mortality were observed. and are in concordance with the current version of Thera- Although there are insufficient data to make a recom- peutic Guidelines: antibiotic, version 15.94 mendation regarding the use of adjuvant corticosteroids Intravenous pentamidine has been shown to have in patients with PJP and malignancy, it may be appropri- similar efficacy to TMP-SMX in HIV-infected individuals ate to co-administer corticosteroids, at doses used in HIV- with PJP.106,107 A retrospective review of first- and second- associated PJP, in patients with moderate to severe PCP. line therapy for HIV-associated PJP108 found higher rates of unchanged second-line therapy with pentamidine than with TMP-SMX; however, survival rates were sig- Alternative agents for the treatment of PJP in nificantly lower when compared with TMP-SMX and the setting of TMP-SMX intolerance clindamycin-primaquine. Pentamidine was associated Desensitisation should be considered for all patients with a higher risk of death (RR 3.3, 95% CI 2.2–5.0). A with TMP-SMX-associated rash but is contraindicated in comparison of aerosolised and reduced-dose intravenous those with a prior history of associated drug rash with pentamidine therapy in patients with mild to moderate eosinophilia and systemic symptoms (‘DRESS’), Stevens- disease found higher rates of early recrudescence and Johnson syndrome or toxic epidermal necrolysis. If TMP- relapse in the aerosolised group.109 SMX remains contraindicated, alternative agents include Clindamycin-primaquine was compared with TMP- atovaquone, clindamycin plus primaquine and dapsone SMX in a randomised study of mild and moderately plus trimethoprim, although there is extremely limited severe PJP in HIV-infected individuals.110 In a study evidence for efficacy in children, and limited data for limited by sample size, efficacy of clindamycin- safety in children with cancer (grade D recommenda- primaquine was similar to oral TMP-SMX or dapsone- tion). Few clinical studies have assessed second-line trimethoprim for treatment of mild-moderate PJP in therapies in patients with malignancy. Therefore, recom- HIV-infected individuals in terms of dose-limiting toxic- mendations for second-line therapy are based on data ity, therapeutic failure or survival.95 Notably, serious

© 2014 The Authors Internal Medicine Journal © 2014 Royal Australasian College of Physicians 1357 Cooley et al. haematological toxicity (neutropenia, thrombocytopenia outbreaks of infection among kidney transplant and methemoglobinaemia) was more common in the patients.118–121 The predominant method of spread for clindamycin-primaquine arm. Pneumocystis is believed to be person-to-person transmis- While dapsone has been shown to be an ineffective sion through exhaled air. Airborne transmission has been treatment as a single agent, a combination of oral demonstrated in animal studies, and air samples from the dapsone plus trimethoprim was effective in patients with rooms of patients with PJP have shown the presence of HIV-associated PJP.111 Major toxicity was seen in only like organisms in air as far as 8 metres from the patient, 13% of patients. Dapsone-trimethoprim has been shown suggesting that this may be a route of transmission.122–124 to be equivalent to TMP-SMX and clindamycin- It is possible that symptomatic patients might be at higher primaquine in mild-moderate disease.95 risk of transmission because of apparent higher density of Atovaquone (750 mg TDS) has been compared with colonisation.17,125 TMP-SMX in a randomised trial of HIV-infected individ- Staff members and other patients may be at risk uals with mild-moderate PJP.96 Non-response rates were of becoming colonised from direct or indirect contact significantly higher in the atovaquone arm, although tol- with an infected patient.126 However, colonisation of erability was greater than with TMP-SMX. Overall suc- healthy humans and previously infected patients is fre- cessful therapy, defined by clinical response and no quent, without placing individuals at risk of subsequent adverse events, was equivalent. infection. Most cases of PJP occur sporadically, without Animal studies have demonstrated that echinocandins, a known infected contact.127,128 which target ß(1,3)-D-glucan, have activity against PJP outbreaks in other patient populations (predomi- P. jirovecii;112 however, clinical trials in humans have not nantly renal transplantation) have been reported, sug- been performed. Data regarding efficacy are restricted to gesting person-to-person transmission on the basis of case reports, and these have revealed inconsistent epidemiology and molecular testing.119,125,129–131 However, responses.113–116 Echinocandins cannot be recommended epidemiologically distinct cases with identical molecular at this time due to their high cost, lack of an oral formu- types may also occur.118 lation and the absence of compelling evidence demon- While some clinicians and institutions recommend that strating their efficacy (grade D recommendation). at-risk patients should not share a hospital room with a patient with known PJP, the current evidence is insufficient to mandate isolation in haematology and solid- Managing PJP treatment failure tumour groups. It is important that patients at risk of PJP Clinical failure is defined as lack of improvement or wors- are identified and receive prophylaxis. ening of respiratory function documented by reduced arterial oxygen saturation after at least 4–8 days of Conclusion Pneumocystis treatment. Early and reversible deterioration in the first 3–5 days is typical, and clinicians should wait Patients with haematological and solid-organ tumours at least 4–8 days before changing therapy due to lack of are highly susceptible to PJP due to disease- and improvement. Although evidence is limited, intravenous treatment-related immunosuppression. In this patient pentamidine, clindamycin-primaquine or addition of an population, PJP is associated with high morbidity and echinocandin can be considered for salvage therapy in mortality. Appropriate prophylaxis for all moderate- to cases of treatment failure.117 high-risk patients is a key strategy for improving out- Treatment failure due to drug intolerance appears less comes, given the proven efficacy of this approach. TMP- common in malignancy-associated PJP than in HIV infec- SMX is the drug of choice for both prophylaxis and tion. Relapse has been reported only rarely in non-HIV treatment, although several alternative agents are avail- associated PJP. able, as outlined here.

PJP infection-prevention measures Acknowledgements A role for isolation precautions to prevent inter-patient The authors would like to thank members of ALLG, ASID transmission of PJP has not been established for patients and ANZCHOG for their review of the draft document, with malignancy, although there are data that suggest and Dr Candice O’Sullivan from Wellmark Pty Ltd for her good infection-control measures prevent transmission in assistance in preparing the manuscript for submission.

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