Pneumocystis pneumonia remains the most prevalent opportunisticinfection in patients infected with the human immunodeficiencyvirus (HIV).1,2 First identified as a protozoan nearly 100 yearsago and reclassified as a fungus in 1988, pneumocystis cannotbe propagated in culture.3,4,5,6 Few treatment options existfor patients with pneumocystis pneumonia. The number of patientswho are receiving chronic immunosuppressive medication or whohave an altered immune system and are thus at risk for pneumocystispneumonia is rapidly growing.2 Although the prevalence of theacquired immunodeficiency syndrome (AIDS) has decreased in theWestern hemisphere owing to the routine use of highly activeantiretroviral therapy (HAART), many patients worldwide do nothave the resources for HAART.1The increased reservoir for infectionamong such patients leads to concern that resistance to trimethoprim–sulfamethoxazole,the most common treatment for pneumocystis pneumonia, will emerge,although this has yet to happen. The application of moleculartechniques to the study of pneumocystis has provided new insightsinto the complex cell biology of this fungus. In this articlewe summarize advances that have resulted from studies of thecell biology, biochemistry, and genetics of pneumocystis inthe past several years and include recommendations for the diagnosisof pneumocystis pneumonia, as well as for prophylaxis and treatment.
Figure 1. Posteroanterior Chest Radiograph of a 68-Year-Old Patient with Pneumocystis Pneumonia That Developed as a Consequence of Long-Term Corticosteroid Therapy for an Inflammatory Neuropathy.
Mixed alveolar and interstitial infiltrates are more prominent on the right side than on the left.
Diagnosis of Pneumocystis Infection
Pneumocystis pneumonia may be difficult to diagnose owing tononspecific symptoms and signs, the use of prophylactic drugsin the treatment of HIV-infected patients, and simultaneousinfection with multiple organisms (such as cytomegalovirus)in an immunocompromised host. The diagnosis of pneumocystispneumonia therefore requires microscopical examination in orderto identify pneumocystis from a clinically relevant source suchas specimens of sputum, bronchoalveolar fluid, or lung tissue,because pneumocystis cannot be cultured (Figure 2).16
Figure 2. Detection of Pneumocystis Forms with the Use of Different Stains.
Panel A shows typical pneumocystis cyst forms in a bronchoalveolar-lavage specimen stained with Gomori methenamine (x100). Thick cyst walls and some intracystic bodies are evident. Wright–Giemsa staining can be used for rapid identification of trophic forms of the organisms within foamy exudates, as shown in Panel B (arrows), in bronchoalveolar-lavage fluid or induced sputum but usually requires a high organism burden and expertise in interpretation (x100). Calcofluor white is a fungal cyst-wall stain that can be used for rapid confirmation of the presence of cyst forms, as shown in Panel C (x400). Immunofluorescence staining, shown in Panel D, can sensitively and specifically identify both pneumocystis trophic forms (arrowheads) and cysts (arrows) (x400).
Sputum induction with hypertonic saline has a diagnostic yieldof 50 to 90 percent and should be the initial procedure usedto diagnose pneumocystis pneumonia, particularly in patientswith AIDS.17 If the initial specimen of induced sputum is negativefor pneumocystis, then bronchoscopy with bronchoalveolar lavageshould be performed. Transbronchoscopic or surgical lung biopsyis rarely needed.18 Trophic forms can be detected with modifiedPapanicolaou, Wright–Giemsa, or Gram–Weigert stains.Cysts can be stained with Gomori methenamine silver, cresylecht violet, toluidine blue O, or calcofluor white. Monoclonalantibodies for detecting pneumocystis have a higher sensitivityand specificity in induced-sputum samples than conventionaltinctorial stains have, but the difference is much less in bronchoalveolar-lavagefluid.19,20 An advantage of monoclonal antibodies is their abilityto stain both trophic forms and cysts, which is important becausethe trophic forms are generally more abundant during pneumocystispneumonia.
The use of the polymerase chain reaction (PCR) to detect pneumocystisnucleic acids has been an active area of research. PCR has beenshown to have greater sensitivity and specificity for the diagnosisof pneumocystis pneumonia from specimens of induced sputum andbronchoalveolar-lavage fluid than conventional staining whenPCR primers for the gene for pneumocystis mitochondrial large-subunitribosomal RNA (rRNA) are used.21,22 In patients with positivePCR results in bronchoalveolar-lavage fluid or sputum but withnegative smears, clinical management of the disease remainsa challenge. However, we recommend treatment of these patientsif immunosuppression is ongoing.23PCR testing of serum samplesis not yet useful.24
Although an elevated serum lactate dehydrogenase level has beennoted in patients with pneumocystis pneumonia, it is likelyto be a reflection of the underlying lung inflammation and injuryrather than a specific marker for the disease.25 Lower levelsof plasma S-adenosylmethionine were observed in seven patientswith confirmed pneumocystis pneumonia than in patients withother pulmonary infections, but the usefulness of this testwill need to be confirmed in a larger cohort of patients.26
Prophylaxis and Treatment of Pneumocystis Pneumonia
Table 1. Drugs for Prophylaxis against Pneumocystis Pneumonia.
Patients who are not infected with HIV but are receiving immunosuppressivemedications or who have an underlying acquired or inheritedimmunodeficiency should receive prophylaxis against pneumocystispneumonia. In a retrospective series, a corticosteroid dosethat was the equivalent of 16 mg of prednisone or more for aperiod of eight weeks was associated with a significant riskof pneumocystis pneumonia in patients who did not have AIDS.12Similar observations have been noted in patients with canceror with connective-tissue disease that was treated with corticosteroids.2,11The notion that trimethoprim–sulfamethoxazole is contraindicatedfor pneumocystis pneumonia prophylaxis in patients treated withmethotrexate may be outdated, because in patients treated withup to 25 mg of methotrexate per week who received prophylaxis,severe myelosuppression did not develop.27 Such patients needto receive folate supplementation (1 mg per day), or leucovorinon the day after receiving methotrexate, and careful monitoringof the results of complete blood counts and liver-function testsis necessary.
The transmission of pneumocystis is not fully understood, norhas its environmental niche been identified. For decades, thetheory of the reactivation of latent pneumocystis infection— which held that pneumocystis remained latent withina person and caused disease when the immune system failed —was popular. Now there is evidence that person-to-person transmissionis the most likely mode of acquiring new infections, althoughacquisition from environmental sources may also occur.29 Inaddition, people who are not infected may be asymptomatic carriersof pneumocystis.30,31,32,33,34,35 Although the results of studiesin animals and humans favor airborne transmission, respiratoryisolation for patients with pneumocystis pneumonia is not currentlyrecommended.
The emerging resistance to trimethoprim–sulfamethoxazoleis being investigated with the use of molecular techniques tostudy mutations in the dihydropteroate synthase gene, whichencodes the enzyme inhibited by dapsone and sulfamethoxazole.Several reports have implicated specific mutations in dihydropteroatesynthase that are associated with the failure of prophylaxisand treatment, an increase in the risk of death, and the selectionof the dihydropteroate synthase mutations by exposure of patientsto sulfa-containing drugs.36,37,38 One study, however, foundno association between trimethoprim–sulfamethoxazole anddihydropteroate synthase mutations, treatment failure, or death.39Because most patients harboring pneumocystis that contains dihydropteroatesynthase mutations still have a response to treatment with trimethoprim–sulfamethoxazole,further research is necessary to determine the importance ofthese mutations and whether the geographic variation of pneumocystisinfection and of other mutations contribute when clinical treatmentfails.
The Biology of the Parasite
The full identification and classification of pneumocystis tookmany decades. Pneumocystis organisms were first identified byCarlos Chagas in the early 20th century, with the use of a guinea-pigmodel of trypanosome infection, and subsequently by AntonioCarinii, in infected rat lungs.4,5 Both investigators believedthey had identified new forms of trypanosomes. Several yearslater, however, the Delanoës recognized that Chagas andCarinii had identified a new species with a unique tropism forthe lung; hence, the new species was named Pneumocystis carinii.3Pneumocystis was initially misclassified as a protozoan on thebasis of the morphologic features of the small trophic form,the larger cyst form, the development of up to eight progenywithin the cyst, and the rupture of the cyst to release newtrophic forms. In 1988, an analysis of the small rRNA subunitfrom pneumocystis pneumonia established a phylogenetic linkageto the fungal kingdom, and all subsequent genomic informationhas corroborated pneumocystis's home within the ascomycetousfungi.6
Pneumocystis organisms have been identified in virtually everymammalian species. In humans, serologic surveys have shown nearlyuniversal seropositivity to pneumocystis in tested populationsby two years of age.40 Pneumocystis organisms encompass a familyof organisms that have a range of genetic characteristics andthat are host-specific. For example, the pneumocystis that infectshumans, which was recently renamed P. jirovecii, cannot infectthe rat, and vice versa.41 The reason for this stringent hostspecificity is unclear. The use of binomial nomenclature forhuman pneumocystis may be of less importance currently, giventhat visualization of the organism is required for the diagnosisof pneumonia.42,43 When PCR has been applied to pneumocystispneumonia in humans, only P. jirovecii has been found, and forthat reason, specifying the name of the species will becomeimportant only if additional species of pneumocystis are foundto infect humans.
The major obstacle to studying pneumocystis is the inabilityto achieve sustained propagation of the organism outside thehost lung.16 Many investigators have attempted to cultivatepneumocystis using a variety of techniques, but none have beensuccessful. Cell-free systems that use media preparations forgrowing protozoa, bacteria, and fungi and tissue-culture systemsin which a variety of cell lines are used have not been successful.Attempts to simulate the intraalveolar environment and to supplementmedia with numerous additives, such as surfactant, lung homogenates,or various chemical compounds, have also proved unhelpful. Untilthe organism can be cultivated in vitro, the infected-animalmodel of pneumocystis pneumonia will remain the source of organismsfor study.
Pneumocystis has a unique tropism for the lung, where it existsprimarily as an alveolar pathogen without invading the host.In rare cases, pneumocystis disseminates in the setting of severeunderlying immunosuppression or overwhelming infection.44 Microscopically,one can identify the small trophic forms (1 to 4 µm indiameter) and the larger cysts (8 µm in diameter). Electronmicroscopical studies have shown three stages of precysts, theearly, intermediate, and late stages (Figure 3).45,46,47 Thetrophic forms are predominantly haploid, though diploid formsalso exist, whereas the cyst contains two, four, or eight nuclei.48
The life cycle of pneumocystis is complex, and several forms are seen during infection. The electron micrograph in Panel A shows a trophic form that is tightly adherent to the alveolar epithelium by apposition of its cell membrane with that of the host lung cell membrane. During infection, trophic forms are more abundant than cysts (approximately 9:1), and the majority of the trophic forms are believed to be haploid during normal growth, with a smaller fraction that are diploid. Trophic forms attach to one another, as shown in the electron micrograph in Panel B, and clusters of clumped trophic forms can be seen during infection. The events that lead to the formation of the cyst, shown in the electron micrograph in Panel C, are unclear, but we hypothesize that the trophic forms conjugate and mature into cysts, which contain two, four, or eight nuclei as they mature.
The availability of molecular techniques has led to major advancesin our understanding of the biology of pneumocystis in the pastseveral years. Key molecules have been identified in the mitoticcell cycle, cell-wall assembly, signal-transduction cascades,and metabolic pathways. The use of heterologous fungal systemsto study the expression of pneumocystis genes has helped thiseffort, but standard biochemical and genetic analysis withinthe organism will be necessary to confirm the function of thesemolecules, once it becomes possible to culture pneumocystis.
The first specific molecule identified from pneumocystis wasa glycoprotein with an apparent molecular mass under reducingconditions of 95 to 120 kD.49,50 Termed glycoprotein A, or majorsurface glycoprotein, this molecule is heavily glycosylatedwith mannose-containing carbohydrates and has an integral rolein the attachment of pneumocystis to host cells.50,51,52,53,54Glycoprotein A consists of a mixture of proteins that are encodedby a family of genes in pneumocystis, but only a single glycoproteinA is expressed by pneumocystis at any one time.55,56 This surfaceglycoprotein is immunogenic and antigenically distinct in everyform of pneumocystis infecting various mammalian hosts.49,57,58The major component of the cyst cell wall is beta-1,3-glucan,which is composed of homopolymers of glucose molecules witha beta-1,3-linked carbohydrate core and side chains of beta-1,6-and beta-1,4-linked glucose.59
The cyst wall also contains chitins and other complex polymers,including melanins. In addition to providing the cell wall withstability, pneumocystis glucan is at least partly responsiblefor the marked inflammatory response in the lungs of the infectedhost.60,61 The pneumocystis beta-1,3-glucan synthetase gene,GSC1, mediates the polymerization of uridine 5'-diphosphoglucoseinto beta-1,3-glucan.62 Inhibitors of beta-1,3-glucan synthetaseare effective in clearing the cystic forms of pneumocystis fromthe lungs of infected animals.63,64 Perturbation of the pneumocystiscell-wall assembly represents an attractive target for the treatmentof pneumocystis pneumonia, because the biosynthetic machineryfor generating glucan is not present in mammals.
Because currently it is not possible to grow pneumocystis outsidean infected host, the functional analysis of the pneumocystiscell cycle and of signal-transduction molecules has been performedwith the use of heterologous expression in related fungi. Thepneumocystis cdc2 cyclin-dependent kinase, cdc13 B-type cyclin,and cdc25 mitotic phosphatase all complement the function ofcell-cycle regulation in yeast that harbor mutations for thesegenes.65,66,67 Fungi use mitogen-activated protein kinase signal-transductioncascades to regulate the cellular responses for mating, environmentalstress, cell-wall integrity, and pseudohyphal or filamentousgrowth. Mitogen-activated protein kinase molecules homologousto those found in mating and cell-wall-integrity pathways havebeen identified in pneumocystis.68,69,70 The gene encoding pneumocystismitogen-activated protein kinase (PCM) functionally complementspheromone signaling in Saccharomyces cerevisiae.70 Furthermore,the finding of enhanced activity of PCM in trophic forms ascompared with that in cysts suggests that the trophic formsuse this pathway for transitions in the life cycle of the organism.70In the cell-wall integrity pathway, the kinases Bck1 and Mpk1function in response to elevated temperature.68,71,72
The trophic forms of pneumocystis adhere tightly to the alveolarepithelium as the infection becomes established. The bindingof pneumocystis to epithelial cells in the lung activates specificsignaling pathways in the organisms, including the gene encodingPCSTE20 kinase, which signal responses for mating and proliferationin fungal organisms.73 Other signaling molecules, includingthe putative pheromone receptors, heterotrimeric G-protein subunits,and transcription factors, have also been identified.74,75,76
Investigators are further evaluating specific molecules withinpneumocystis as potential drug targets. These molecules includedihydrofolate reductase, the product of which is the targetof trimethoprim; thymidylate synthase; inosine monophosphatedehydrogenase, which is inhibited by mycophenolic acid; S-adenosyl-L-methionine:sterolC-24 methyl transferase, which is involved in the biosynthesisof sterol; and lanosterol 14-demethylase, the target enzymeof azole antifungal compounds.77,78,79,80 With work on the cloningof the pneumocystis genome continuing, the identification ofadditional treatment targets is anticipated.
Host Response to Pneumocystis Infection
Effective inflammatory responses in the host are required tocontrol pneumocystis pneumonia. Exuberant inflammation, however,also promotes pulmonary injury during infection. Severe pneumocystispneumonia is characterized by neutrophilic lung inflammationthat may result in diffuse alveolar damage, impaired gas exchange,and respiratory failure. Indeed, respiratory impairment anddeath are more closely correlated with the degree of lung inflammationthan with the organism burden in pneumonia.9 Although patientswith neutropenia occasionally become infected with pneumocystis,they do not appear to be inordinately predisposed to this infectionas compared with other groups of immunosuppressed patients.
Lymphocyte Responses to Pneumocystis
Immune responses directed against pneumocystis involve complexinteractions between CD4+ T lymphocytes, alveolar macrophages,neutrophils, and the soluble mediators that facilitate the clearanceof the infection. In particular, the activity of CD4+ T cellsis pivotal in the host's defenses against pneumocystis, in bothanimals and humans, and the risk of infection increases witha CD4+ count of less than 200 per cubic millimeter.7,81 CD4+cells function as memory cells that orchestrate the host's inflammatoryresponses by means of the recruitment and activation of otherimmune effector cells, including monocytes and macrophages,to attack the organism. Mice with severe combined immunodeficiency(SCID) lack functional T and B lymphocytes, and spontaneouspneumocystis infection may develop in them by three weeks ofage, providing an excellent model for understanding the functionof lymphocytes in this disease.82 SCID mice have progressivepneumocystis infection, despite the presence of otherwise functionalmacrophages and neutrophils.82,83 When the immune system isreconstituted with the use of CD4+ spleen cells, however, themice regain the ability to clear infection effectively.84,85
The mechanisms by which CD4+ cells mediate a defense againstpneumocystis have only begun to emerge in recent years. Macrophage-derivedtumor necrosis factor (TNF-) and interleukin-1 are believedto be necessary for initiating pulmonary responses to pneumocystisinfection that are mediated by CD4+ cells. The cells proliferatein response to pneumocystis antigens and generate cytokine mediators,including lymphotactin and interferon gamma.85 Lymphotactin,a chemokine, acts as a potent chemoattractant for further lymphocyterecruitment in pneumocystis pneumonia.86 Interferon gamma stronglyactivates the macrophage production of TNF-, superoxides, andreactive nitrogen species, each of which is implicated in thehost defense against pneumocystis.87,88 Aerosolized interferongamma reduces the intensity of infection in rats infected withpneumocystis, regardless of the degree of CD4+ depletion.87
Although T lymphocytes are essential for the clearance of pneumocystis,data suggest that T-cell responses may also result in substantialpulmonary impairment during pneumonia. For instance, in SCIDmice infected with pneumocystis, normal oxygenation and lungfunction occur despite active infection until the late stagesof the disease.83 When the immune systems in these animals arereconstituted with the use of intact spleen cells, an intenseT-cell–mediated inflammatory response ensues, resultingin substantially impaired gas exchange.83 In the absence ofbrisk lung inflammation, pneumocystis has little direct effecton pulmonary function. In a similar manner, in patients whohave undergone bone marrow transplantation the clinical onsetof pneumocystis pneumonia and of most marked alterations inlung function occur during engraftment.89 Pneumocystis pneumoniaalso results in the marked accumulation of CD8+ T lymphocytesin the lung.90
Macrophages in Host Defense against Pneumocystis
Alveolar macrophages are the principal phagocytes mediatingthe uptake and degradation of organisms in the lung. When thereare no opsonins in the epithelial-lining fluid, the uptake ofpneumocystis is mediated mainly through the macrophage mannosereceptors, pattern-recognition molecules that interact withthe surface mannoprotein, glycoprotein A.52,91 After they havebeen taken up by macrophages, pneumocystis organisms are incorporatedinto phagolysosomes and degraded.92
The function of macrophages is impaired in patients with AIDS,malignant disease, or both, resulting in the reduced clearanceof pneumocystis.93 In macrophage-depleted animals the resolutionof pneumocystis infection is impaired.92 Macrophages producea large variety of proinflammatory cytokines, chemokines, andeicosanoid metabolites in response to phagocytosis of pneumocystis.92Although these mediators participate in eradicating pneumocystis,they also promote pulmonary injury.
Cytokine and Chemokine Networks
TNF- has important effects during pneumocystis pneumonia.94,95The clearance of pneumocystis is delayed when TNF- is neutralizedby antibodies or inhibitors in animals with pneumocystis pneumonia.95,96TNF- promotes the recruitment of neutrophils, lymphocytes, andmonocytes. Although their recruitment is important for clearanceof the organisms, these cells injure the lung by releasing oxidants,cationic proteins, and proteases. TNF- also induces the productionof other cytokines and chemokines, including interleukin-8 andinterferon gamma, which stimulate the recruitment and activationof inflammatory cells during pneumocystis pneumonia.
The cell wall of pneumocystis contains abundant beta-glucans,and studies have confirmed that the production of TNF- by alveolarmacrophages is mediated by recognition of the beta-glucan componentsof pneumocystis.60 Macrophages display several potential receptorsfor glucans, including CD11b/CD18 integrin (CR3), dectin-1,and toll-like receptor 2.97,98 The activation of macrophagesby pneumocystis is augmented by proteins in the host such asvitronectin and fibronectin that bind the glucan componentson the organism.99
The cysteine–X amino acid–cysteine chemokines, suchas interleukin-8, macrophage-inflammatory protein 2, and theinterferon-inducible protein of 10 kD, which are potent chemoattractantsfor neutrophils, are important during pneumocystis infection.Interleukin-8 is correlated with both neutrophil infiltrationof the lung and impaired gas exchange during severe pneumocystispneumonia. Furthermore, the level of interleukin-8 in bronchoalveolar-lavagefluid may serve as a predictor of severe respiratory compromiseand death from the disease.100 Isolated pneumocystis beta-glucanstimulates alveolar macrophages and alveolar epithelial cellsto produce marked quantities of macrophage inflammatory protein2.60,61 The neutrophils recruited into the lungs release reactiveoxidant species, proteases, and cationic proteins, which directlyinjure capillary endothelial cells and alveolar epithelial cells.
Alveolar Epithelial Cells and Proteins
Trophic forms adhere tightly to type I alveolar cells throughinterdigitation of their membranes with those of the host.101The binding of pneumocystis to the epithelium is facilitatedby interactions of proteins in the host, such as fibronectinand vitronectin, that bind to the surface of pneumocystis andmediate the attachment to integrin receptors present on thealveolar epithelium.102 In infected tissues, type I alveolarcells with adherent pneumocystis appear vacuolated and eroded.103However, studies of cultured lung epithelial cells have shownthat the adherence of pneumocystis alone does not disrupt thestructure or barrier function of alveolar epithelial cells,though proliferative repair of the epithelium is reduced.104,105It is therefore unlikely that the adherence of pneumocystisto alveolar epithelium is by itself responsible for the diffusealveolar damage in severe pneumonia. Rather, the inflammatoryresponses in the host are primarily responsible for the compromiseof the alveolar-capillary surface.
Electron microscopical studies have shown that pneumocystisorganisms are embedded in protein-rich alveolar exudates, whichcontain abundant fibronectin, vitronectin, and surfactant proteinsA and D.106,107 In contrast, surfactant protein B is reducedduring pneumonia.108 Both surfactant protein A and surfactantprotein D interact with the glycoprotein A components of thesurface of pneumocystis.52,106 Surfactant protein A modulatesthe interactions of pneumocystis with the alveolar macrophages.109,110In contrast, surfactant protein D mediates the aggregation ofthe pneumocystis organisms,111 but because the aggregated organismsare extremely poorly taken up by macrophages, many organismsmay escape elimination.111 Pulmonary surfactant phospholipids,which contribute to the low surface tension in the alveoli,are reduced during pneumocystis pneumonia, and abnormalitiesin the composition and function of the surfactant are the resultof the host's inflammatory response to pneumocystis, ratherthan direct effects of the organisms on the surfactant components.112
Summary
Pneumocystis pneumonia remains a serious cause of sickness anddeath in immunocompromised patients. The epidemiology of thisinfection is only beginning to emerge, but it includes the transmissionof organisms between susceptible hosts as well as probable acquisitionfrom environmental sources. Lung injury and respiratory impairmentduring pneumocystis pneumonia are mediated by marked inflammatoryresponses in the host to the organism. Trimethoprim–sulfamethoxazolewith adjunctive corticosteroid therapy to suppress lung inflammationin patients with severe infection remains the preferred treatment.However, accumulating evidence of mutations of the gene thatencodes dihydropteroate synthase in pneumocystis has arousedconcern about the potential for the emergence of resistanceto sulfa agents, which have been the mainstay of prophylaxisand treatment of pneumocystis pneumonia. An improved understandingof the basic biology of pneumocystis has helped to define newtargets for the development of drugs to treat this importantinfection.
Supported by grants (R01 AI-48409 to Dr. Thomas and R01 HL 62150and R01 HL 55934 to Dr. Limper) from the National Institutesof Health.
We are indebted to Pawan K. Vohra, Robert Vassallo, and TheodoreJ. Kottom for many helpful discussions.
Source Information
From the Thoracic Diseases Research Unit, Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine (C.F.T., A.H.L.), and the Department of Biochemistry and Molecular Biology (A.H.L.), Mayo Clinic College of Medicine, Rochester, Minn.
Address reprint requests to Dr. Limper at 8-24 Stabile Bldg., Mayo Clinic, Rochester, MN 55905, or at limper.andrew{at}mayo.edu.
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Pneumocystis Pneumonia
del Rio C., Barragan M., Franco-Paredes C., Udwadia Z. F., Doshi A. V., Bhaduri A. S., van Well G., van Furth M.
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351:1262-1263, Sep 16, 2004.
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A correction has been published: N Engl J Med 2004;351(4):408.
-demethylase, the target enzyme of azole antifungal compounds.77,78,79,80 With work on the cloning of the pneumocystis genome continuing, the identification of additional treatment targets is anticipated. 
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