pneumocystis carinii infection: current treatment and prevention

Journal of Antimicrobial Chemotherapy (1996) 37, Suppl. B, 33-53

Pneumocystis carinii infection: current treatmentand prevention

Robert F. Miller***, Jo Le Noury*, Elizabeth L. Corbetf, J. Mark Felton' andKevin M. De Cock'

'Departments of Medicine and bAcademic Genitourinary Medicine, University CollegeLondon Medical School and 'Department of Clinical Sciences, London School of TropicalMedicine and Hygiene, Camden and Islington Community Health Services NHS Trust,

Middlesex Hospital Site, London WIN 8AA, UK

Pneumocystis carinii is a common cause of pneumonia in individuals who areimmunosuppressed by HIV infection. Use of molecular biological techniques showthat P. carinii is a fungus and that infection in man is not a zoonosis. Invasive testssuch as sputum induction or bronchoscopy are used to make the diagnosis of P.carinii pneumonia. Life long primary prophylaxis is given to HIV positive individualswith CD4+ lymphocyte counts <0.20 x 1O'/L or a CD4: total lymphocyte ratio of<1.5, constitutional symptoms, or with other AIDS defining diseases. Secondaryprophylaxis is given after a first episode to prevent a recurrence. First choice forprimary and secondary prophylaxis is oral co-trimoxazole 960 mg od or threetimes a week. In patients who are intolerant to co-trimoxazole, nebulisedpentamidine or dapsone (with or without pyrimethamine) are second and thirdchoices. In a patient with acute PCP disease, severity should be assessed usingclinical, radiographic and blood gas criteria as those with moderate or severe diseasewill benefit from adjuvant glucocorticoids. Co-trimoxazole (120 mg/kg/day individed doses for 21 days) is first choice therapy for PCP of all degrees of severity.In patients who fail to respond to co-trimoxazole or who are intolerant to it, secondline treatment is iv pentamidine in those with severe disease and oral dapsone withtrimethoprim, oral clindamycin with primaquine or iv pentamidine in those with mildor moderately severe disease.

Introduction

Since its description in 1981 as the first major opportunistic infection of the AIDSepidemic (Gottlieb, Schanker & Fan, 1981), Pneumocystis carinii pneumonia (PCP) hasremained one of the commonest AIDS defining illnesses in developed countries(Hoover et al., 1993). The treatment and prophylaxis of PCP are therefore importantaspects of the current management of HIV infection. This paper reviews clinicalaspects of the treatment and prophylaxis of PCP. The article begins with a briefdiscussion of molecular biology and current diagnostic strategies for diagnosis of P.carinii infection.

'Corresponding author Dr R. F. Miller, Department of Medicine, UCLMS, Middlesex Hospital LondonWIN 8AA, UK. Phone: +44-{171)-390-9442; Fax: +44-{171)-380-9442.

33

0305-7453/96/37BO33 + 21 $12.00/0 £ 1996 The British Society for Antimicrobial Chemotherapy

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34 R. F. Miller et al.

Molecular biology of P. carinii

Infection due to P. carinii results in an eosinophilic intra-alveolar foamy exudate whichis associated with a mild plasma cell interstitial pneumonitis. Two morphological formsof P. carinii are seen in infected lungs: thin walled, irregularly shaped, single nucleatedtrophozoites (2-5 fim) which adhere firmly to type 1 pneumocytes, and thick walledcysts (6-7 /im) containing 4—8 single nucleated sporozoites which lie free within thealveoli (Foley, Griffiths & Miller, 1993).

The P. carinii trophozoites are irregularly shaped, motility organelles are absent, cystwalls can be stained with silver, the organism does not grow on artificial media and issusceptible to anti-protozoal drugs including pentamidine but not to antifungal agentssuch as amphotericin B. These features have lead to the view that P. carinii istaxonomically either a protozoan or a fungus.

Genetic homology

In 1988, 18S ribosomal RNA gene sequences of P. carinii derived from rats were foundto have close homology with those of fungi (Edman et al., 1988). Since this report the18S ribosomal RNA gene from over 120 different species of fungi has been cloned andsequenced. Comparison of the small subunit ribosomal RNA gene sequences from 39species of fungi strongly suggest that P. carinii is a fungus (Van de Peer et al., 1992).Many chromosomal and mitochondrial genes from P. carinii including fl tubulin(Edlind et al., 1992), mitochondrial DNA (Pixley et al., 1991) and AROM (a proteinresponsible for catalysing five consecutive steps of the pre-chorismate pathway offungal aromatic amino acid biosynthesis) (Banerji et al., 1993) have been cloned andsequenced. The sequence data from all of these genes firmly place P. carinii in the fungalkingdom.

Host specificity

P. carinii from one host species will not grow if placed in the lungs of another species,suggesting that there is host specificity. Antigenic differences have been observedbetween P. carinii isolated from different hosts (Kovacs et al., 1988; Bauer et al., 1993).The karyotypes of human- and rat-derived P. carinii have been demonstrated not tobe identical (Hong et al., 1990; Sinclair et al., 1991). Analysis of sequences encodingmitochondrial large subunit robosomal RNA (Sinclair et al., 1991), p tubulin (Edlindet al., 1992) and nuclear ribosomal RNA have shown differences in rat- andhuman-derived P. carinii. The sequences of 18S ribosomal RNA genes from rat- andhuman-derived P. carinii have been compared and found to be 4% divergent (Stringeret al., 1993). In contrast, two species of Candida, Candida albicans and Candidatropicalis, are only 2% divergent at this locus.

Genetic diversity may occur in P. carinii derived from a single host species. Twodistinct types of P. carinii have been found in infected lungs of rat and ferrets and lowlevels of genetic diversity occur in human-derived P. carinii (Lee et al., 1993; Wakefieldet al., 1994). Analysis at a locus encoding the large subunit of mitochondrial ribosomalRNA of human-derived P. carinii from London, UK, Harare, Zimbabwe, Porto Alegre,Brazil and Memphis, USA showed only single base polymorphisms and a lack ofsequence variation among samples obtained over a period of 4 years from London(Wakefield et al., 1994).


P. carinii infection 35

Infection

The hypothesis, that PCP in an immunocompromised individual occurs by reactivationof a childhood-acquired latent infection, is supported by the demonstration ofantibodies against P. carinii in the majority of healthy children (Peglow et al., 1990;Wakefield et al., 1990). However, colonisation by P. carinii of broncho-alveolar lavagefluid or post-mortem lung tissue from immunocompetant individuals cannot bedemonstrated by studies using DNA amplification or monoclonal antibodies (Millard& Heryet, 1988; Peters et al., 1991; Matusiewicz et al., 1994) and the hypothesis isfurther challenged by reports of nosocomial case clusters for PCP (Chave et al., 1991;Jacobs et al., 1991). There is limited persistence of latent P. cariniiin the lungs of steroidimmunosuppressed rats after a primary episode of PCP; at least 75% of animals havecleared P. carinii from their lungs within one year (Vargas et al., 1995).

P. carinii infection in rats is acquired by the airborne route and infection in man isthought to be acquired in the same way. A recent study has shown that DNA sequencesidentical to P. carinii have been detected in samples of the air of rural Oxfordshire(Wakefield, 1995). Changes in environmental humidity and temperature, factors whichare important for growth of fungi and dissemination of spores, may account for theobserved seasonal variation in incidence of PCP (Miller, Grant & Foley, 1992; Hooveret al., 1993).

Transient carriage of P. carinii may occur in the lungs of immunocompetent hosts.P. carinii DNA was detected in the lungs of immunocompetent rats used as sentinelsand housed near immunosuppressed P. carinii infected rats. The DNA disappearedrapidly from the lungs of these sentinel rats after they were housed away from theimmunosuppressed infected animals (Sepkowitz et al., 1993). Immunocompetent healthcare workers in an AIDS unit nursing patients with P. carinii have been shown to havehigher serum antibodies to P. carinii than health care workers caring for the elderly,suggesting that asymptomatic carriage occurs as a result of environmental exposure(Leigh et al, 1993).

In summary P. carinii is a fungus, with different species infecting different hosts.Infection in man is not a zoonosis, nor do the majority of immunocompetent individualsharbour the organism. Clinical pneumonia in the majority of cases is probably due toreinfection rather than reactivation.

Clinical and laboratory diagnosis

There is continuing controversy as to whether all HIV infected patients with suspectedPCP require bronchoscopy to confirm the diagnosis. Some physicians have suggestedthat empirical therapy may be used for HIV-infected patients who have symptoms,radiographic abnormalities and hypoxaemia typical of PCP, without the need forbronchoscopy (Miller et al., 19896; Tu, Biem & Detsky, 1993). Others, however,recommend that the diagnosis should be confirmed in every case by cytological andmicrobiological investigations. Many centres now treat patients with PCP empirically,and perform bronchoscopy only for those who fail to respond (Miller et al., 19896; Tuet al., 1993). However, patients with PCP treated with appropriate therapy typicallytake 4-7 days to show any sign of clinical improvement, and the chest radiograph cantake up to 2 weeks before abnormalities begin to diminish. Thus, a confirmed diagnosisensures that the patient is receiving appropriate treatment especially during the first few



days. In addition, the diagnosis should be considered not only in HIV-positiveindividuals with low CD4 + lymphocyte counts but also in less advanced disease. Thereare reports of PCP occurring with primary HIV infection at the time of seroconversion(Vento et al., 1993), and also in patients without any underlying immune deficit (Jacobset al., 1991).

Several tests help the diagnosis of PCP (Malin & Miller, 1992). Non-invasive tests,which include chest radiology, arterial blood gas tensions, transcutaneous (exercise)oximetry, pulmonary function tests, CT scanning, serum lactate dehydrogenase enzymeassay and nuclear imaging (including Technetium DTPA transfer, Galium 67 citrate andIndium-111-HIG) do not provide a specific diagnosis. Their value lies in determiningthe presence or absence of pulmonary disease, in assessing disease severity, for examplethe degree of hypoxaemia, whether an invasive test is needed for making an aetiologicaldiagnosis, and in monitoring disease progress or response to therapy. Invasive tests,which include sputum induction, fibre optic bronchoscopy with bronchoalveolar lavagewith or without transbronchial biopsy, and open lung biopsy, enable a specific diagnosisto be made (Malin & Miller, 1992).

Sputum induction with hypertonic saline requires special equipment and dedicated,skilled personnel to supervise the procedure. Some centres have had more success withsputum induction than others; compared with fibreoptic bronchoscopy, the yield of P.carinii (and other pathogens) is low (Miller et al., 1991 b) and some patients experiencedyspnoea, retching or unpredictable hypoxaemia (Miller, Buckland & Semple, 1991a).Using of immunofluorescent P. carinii specific monoclonal antibodies and PCR toamplify DNA from P. carinii increases the diagnostic yield from induced sputum(Wakefield et al., 1991).

Fibreoptic bronchoscopy is well established as a diagnostic tool for a large range ofpulmonary disorders, and broncho-alveolar lavage and transbronchial biopsy are widelyused. Broncho-alveolar lavage has been shown to have a very high yield for P. cariniiwhereas the additional benefits of transbronchial biopsy are small and the procedurecarries a high risk of complications including pneumothorax and bleeding (Griffithset al., 1991). Cysts of P. carinii are readily identified by staining with Grocott'smethenamine silver, toluidine blue O or cresyl violet, whereas trophozoites are bestdemonstrated by Giemsa or Diff-Quik (American Scientific Products, McGow Park, IL,USA) (Malin & Miller, 1992; Miller & Mitchell, 1992).

Open lung biopsy has a high diagnostic yield in general medical and HIV-infectedpatients with diffuse lung disease. In HIV-infected individuals morbidity associated withthe procedure, including wound infection, pneumothorax and the need forpost-operative mechanical ventilation is low (Miller, Pugsley & Griffiths, 1995). Mostcentres would only proceed to open lung biopsy in an HIV-infected patient withrespiratory symptoms and a diffusely abnormal chest radiograph if two bronchoscopeswith lavage have failed to establish a diagnosis, or if despite treatment for a confirmedpathogen, the patient continues to deteriorate (Miller et al., 1995).

Prophylaxis of P. carinii pneumonia

Before the onset of the AIDS pandemic, prophylaxis against PCP was used successfullyin patients who were immunosuppressed following organ transplantation or treatmentof malignancy. The progressive nature of HIV related immunodeficiency means that



individuals are increasingly susceptible to infection. Primary prophylaxis is given to HIVinfected individuals who are at risk of developing PCP for the first time, and secondaryprophylaxis is given to prevent recurrence. As prophylaxis is life long, regimens shouldideally be cheap, effective, easily administered in order to optimise compliance, have lowtoxicity and not interact adversely with anti-retroviral therapy.

Primary prophylaxis

In the multi centre AIDS cohort study (MACS) of homosexual and bisexual men, whodid not have AIDS nor were taking anti-pneumocystis prophylaxis, the incidence ofPCP rose within 6 months from 0.5% in those with baseline CD4 + lymphocyte counts>0.20 x 109/L (normal range = 0.35-2.2 x 109/L) to 8.4% in those with baselineCD4+ lymphocyte counts <0.20 x 109/L (or a CD4 + to total lymphocyte ratio of< 1:4%) (Phair et al., 1990). Several other points emerged from this study. Firstly, themedian CD4 count at which PCP occurred was below 0.10 x 109/L, suggesting that,were a 'cut ofF of 0.20 x 109/L to be used, some asymptomatic individuals would takepotentially toxic drugs unnecessarily. Secondly, symptoms or signs of oral candidosisor fever independently predicted the development of PCP, as 60% of men with CD4 +lymphocyte counts >0.20 x 109/L had one or both of these symptoms beforedeveloping PCP. Thirdly, a small number of individuals developed PCP with CD4 +lymphocyte counts >0.20 x 109/L (Phair et al., 1990). It is currently recommended thatlife long primary prophylaxis be given to HIV-infected adults who have CD4 +lymphocyte counts <0.20 x 109/L or a C D 4 + : total lymphocyte ratio of <1:4,constitutional symptoms (oral candidosis or fever of unknown origin defined by atemperature of ^37.8°C for ^ 2 weeks), regardless of CD4+ lymphocyte counts, orthose with other diseases such as Kaposi's sarcoma or cerebral toxoplasmosis whichdefine AIDS (US Public Health Service Task Force, 1993; Miller, 1994).

Secondary prophylaxis

Following an episode of PCP without secondary prophylaxis the risk of recurrence isup to 60% at 12 months (Kovacs & Masur, 1988). Secondary prophylaxis should begiven after an episode of PCP (US Public Health Service Task Force, 1993; Miller,1994).

Drugs for prophylaxis (see Table I)

Co-trimoxazole

Co-trimoxazole given by mouth in a dosage of 960 mg (800 mg of sulphamethoxazoleand 160 mg of trimethoprim) once daily or three times a week is the combination ofchoice for both primary and secondary prophylaxis against PCP. Trimethoprim is notan effective drug when used alone for P. carinii prophylaxis or treatment (Waltzer el al.,1992).

An unblinded randomised study of primary prophylaxis with co-trimoxazole 960 mgtwice daily in 60 patients with Kaposi's sarcoma showed that 16 of 30 subjects notreceiving prophylaxis developed PCP during 2 years follow up, whereas none of the30 patients receiving co-trimoxazole did (Fischl, Dickinson & La Voie, 1988).



Adverse reactions occurred in 50% of the patients taking co-trimoxazole and inone-third of these the drug had to be stopped (Fischl et al., 1988).

The Dutch AIDS Treatment Group's randomised study compared the efficacy andtoxicity of oral co-trimoxazole given orally at 480 or 960 mg once daily, with that ofnebulised pentamidine, 300 mg per month administered by a Respirgard II jet nebuliser,in 213 HIV infected individuals with CD4+ counts <0.20 x 10'/L and no previousPCP (Schneider et al., 1992). During a mean follow up of 9 months, 6 (11%) of thosereceiving pentamidine developed PCP, but none of those receiving either dosage ofco-trimoxazole did. The cumulative incidence of toxic events in the first 3 months was3%, 21%, and 26% for pentamidine, low and high dosage co-trimoxazole, respectively.Adverse reactions occurred sooner in patients treated with 960 mg compared with thosetreated with 480 mg of co-trimoxazole. Co-trimoxazole 960 mg three times per week hasbeen compared prospectively with pentamidine 300 mg inhaled monthly and a regimenof dapsone 100 mg daily and pyrimethamine 25 mg once a week (Mallolas et al., 1993).The attack rate for P. carinii in those given co-trimoxazole was 3% per year of followup but there were more adverse reactions amongst those who received co-trimoxazoleor dapsone with pyrimethamine, and treatment was more likely to be discontinuedcompared with those receiving inhaled pentamidine.

Table I. Prophylaxis of P. carinii pneumonia

First line

Second line

Third line

Fourth line

Fifth line

Anecdotal

Drug

co-trimoxazole

pentamidine

dapsonewith or withoutpyrimethamine

pentamidine

sulfadoxine andpyrimethamine

dapsone withtrimethoprimatovaquone

clindamycin withprimaquine

Dose

960 mg od

300 mgonce amonth

100 mg od

300 mgonce every2-4 weeks

1 g and50 mg,

both oncea week

100 mg od20 mg/kg od750 mg tds

300-450 mg tds-qds15 mg od

Route

oral

jetnebuliser

oral

iv or im

oraloral

oraloraloraloraloral

Comment

480 mg od or960 mg three times aweek may be equally

effective. Mayprotect against

bacterial infectionand reactivation of

cerebral toxoplasmosisconsider increasingdose frequency tofortnightly if CD4

count <0.05 x 10'/Lpyrimethamine may

protect against react-ivation of cerebral

toxoplasmosismay cause severe

side-effects

less effective thanother regimens


P. carinii Infection 39

With intermittent therapy, a potential problem is that missing any one of the dosesmay result in inadequate prophylaxis and breakthrough infection.

The efficacies of co-trimoxazole 960 mg once daily, dapsone 100 mg once dailyand nebulised pentamidine 300 mg per month were compared as primary prophylaxisin 843 HIV infected patients with CD4+ counts <0.20 x 10'/L who werereceiving zidovudine. The 36 month cumulative risk of PCP was 18%, 17% and 21%among those receiving co-trimoxazole, dapsone and pentamidine, respectively. Of thosewith CD4+ lymphocyte counts <0.10 x lO'/L at entry to the study, the risk of anepisode of PCP was 33%, 19% and 22% among those given nebulised pentamidine,co-trimoxazole and dapsone, respectively (P < 0.05) (Bozzette et al., 1995).

The AIDS Clinical Trials Group Study O21 compared oral co-trimoxazole 960 mgdaily with monthly nebulised pentamidine 300 mg via a Respirgard II nebuliser forsecondary prophylaxis in 310 AIDS patients who were also taking zidovudine (Hardyet al., 1992). After adjusting for CD4+ lymphocyte counts at entry to the study, therisk of recurrent PCP was 3.25 times greater in the pentamidine treatment group. Agreater proportion of those taking co-trimoxazole discontinued medication due totoxicity. Adverse drug reactions during high dose treatment of prior PCP did not predictsubsequent toxicity when co-trimoxazole was used for secondary prophylaxis. Anotheradvantage of co-trimoxazole demonstrated in ACTG O21 was 'cross prophylaxis'—inthat the combination afforded some degree of protection against bacterial infections andtoxoplasmosis (Hardy et al., 1992).

The commonest adverse reactions to co-trimoxazole are fever, skin rash inapproximately 20%, nausea, headache and bone marrow suppression (usuallygranulocytopenia and thrombocytopenia). Rarely, nephritis and biochemical liverfunction abnormalities may occur. All of these side effects are more frequent when thedrug is used for prolonged periods and at higher doses (Masur, 1992).Co-administration of folinic acid supplements does not affect the incidence ofhaematological toxicity.

Nebulised pentamidine

The San Francisco community prophylaxis trial showed that nebulised pentamidineadministered with a Respirgard II at a dose of 300 mg/month was superior to either30 mg or 150 mg given once a fortnight (Leoung et al., 1990). However, the studies ofHardy et al. (1992) and Schneider (1992) have shown that nebulised pentamidine is lesseffective than oral co-trimoxazole for prophylaxis.

The commonest adverse reactions to pentamidine are cough and bronchospasm(Leuong et al., 1990). Hypersalivation, a bitter metallic taste and nausea, which are dueto deposition of drug in the oropharynx, trachea and major bronchi also occur. Mostcentres now routinely give a bronchodilator, such as salbutamol 200 /ig, via a metereddose inhaler before administering the drug. The administration of pentamidine isdictated by the need to deposit pentamidine in the alveoli and not in the oropharynxand upper airways. This makes conventional nebulisers inappropriate as they producean heterogeneous aerosol containing some large particles which will deposit in the upperrespiratory tract. The Respirgard II is a jet nebuliser which employs a series of internalbaffles to limit the passage of larger droplets into the aerosol and so reduce thefrequency of adverse reactions.


40 R. F. Miller et at.

The cost of the nebuliser and the drug itself make nebulised pentamidine prophylaxisapproximately eight times more expensive than treatment with co-trimoxazole (Miller,1994). There is also a potential risk that the process of nebulisation and any associatedcoughing may increase the risk of transmission of respiratory diseases such astuberculosis to other patients or members of staff. Adverse reactions including cough,bronchoconstriction, circumoral paraesthesia, metallic taste and progressive reductionsof gas transfer factor, due to environmental contamination, have been reported amonghealth care workers (HCW) administering or supervising pentamidine nebulisation(Miller & Mitchell, 1992; Miller, 1994). Nebulisation of pentamidine in hospital orout-patient facilities must be carried out in a separate room, ideally with its ownextraction and ventilation system. Having prepared the nebuliser, HCW should leavethe room and not return until nebulisation is complete (Miller & O'Doherty, 1995).

The clinical presentation of PCP may also be altered as a result of nebulisedpentamidine prophylaxis, with an increased proportion of patients having atypicalupper zone chest radiographic abnormalities (Fahy et al., 1992). As very little drug isabsorbed systematically it is unlikely that pentamidine will prevent extrapulmonarypneumocystosis (Coker et al., 1991).

Some centres are now administering pentamidine more frequently, for example300 mg each fortnight to profoundly immunosuppressed patients with CD4 +lymphocyte counts <0.05 x 1O'/L, who are intolerant of co-trimoxazole, although itis not clear whether this policy offers any advantages in terms of less break throughpneumonia (Golden et al., 1993). Combining nebulised pentamidine fortnightly withoral medication such as dapsone 100 mg per day is an alternative strategy for patientswho have had multiple episodes of PCP.

Other drugs

Dapsone. The folate synthesis inhibitor dapsone, which is not licensed in the UK fortreatment or prophylaxis of PCP, has been shown to provide effective primary andsecondary prophylaxis at a dosage of 50 mg or 100 mg daily (Kemper et al., 1990).Dapsone is often combined with pyrimethamine although this appears to add little tothe effect of dapsone against PCP (Falloon et al., 1994). A randomised comparative trialof primary prophylaxis it was shown that, in 362 patients, dapsone 50 mg per day andpyrimethamine 50 mg per week was as effective as nebulised pentamidine (300 mg permonth); 5.5% of patients in each arm developed PCP at 18 months follow up. Nebulisedpentamidine was better tolerated than dapsone with pyrimethamine (Girard et al.,1993). However, the combination appeared to confer protection against reactivation ofcerebral toxoplasmosis. In another study of 226 patients, treatment with dapsone100 mg given three times weekly and pyrimethamine 25 mg once per week was lesseffective than co-trimoxazole 960 mg given three times weekly (Coker et al., 1992).

Parenteralpentamidine. Intravenous (Ena et al., 1994), or intramuscular pentamidine(Cheung et al., 1993), at a dosage of 4 mg per kg body weight given every 2-4 weekshas been used as fourth line treatment in patients intolerant of other therapy, and alsoin those who have experienced breakthrough P. carinii infection whilst taking otherprophylaxis regimens. This method of prophylaxis is associated with the potential forsevere local (phlebitis or muscle abscess) and systemic (dysrrhythmias, hypotension andhypoglycaemia) side-effects.



Others. The combination of sulfadoxine and pyrimethamine appears to be the leasteffective of any regimen (Gottlieb et al., 1984). Evidence for the efficacy of dapsone withtrimethoprim, clindamycin and primaquine and atovaquone is anecdotal.

Treatment

It is important to stratify patients with PCP into those having mild, moderate or severedisease (Table II), as some drugs are known to be ineffective and others are unprovenfor treatment of severe disease. Identification of patients with moderate or severe diseasealso means that adjuvant glucocorticoid therapy may be used.

Co-trimoxazole, dapsone and primaquine should not be used in patients withglucose-6-phosphate dehydrogenase deficiency because they increase the risk ofhaemolysis. Ganciclovir and zidovudine should be stopped when patients are receivinghigh dosage co-trimoxazole because of the potential for severe marrow toxicity.

Table II. Grading of severity of P. carinii pneumonia (cf. Miller & Mitchell, 1992)

Mild Moderate Severe

Symptomsand signs

Arterial oxygentension (PaO2)(at rest)

Arterial oxygensaturation (SaO2)(at rest)

Chest radiograph

dyspnoea onexertion, with or

without coughand sweats

> 11.0 kPa

>96%

normal, orminor perihilar

shadowing

dyspnoea on minimalexertion and occasionallyat rest. Cough and fever

8.0 to ll.OkPa

91 to 96%

diffuse interstialshadowing

dyspnoea andtachypnoea at rest.Persistent fever and

cough

<8.0kPa

extension interstitialshadowing with or

without diffusealveolar shadowing

Co-trimoxazole

Trimethoprim and sulphamethoxazole target sequential steps in the folate synthesispathway. Trimethoprim inhibits dihydrofolate reductase and sulphamethoxazoleinhibits dihydrotperoate synthetase.

Co-trimoxazole is the drug first choice to treat PCP of any severity and a course of21 days is recommended. It can be given in two to four divided doses either iv or orallyin a fixed combination of 100 mg/kg/day sulphamethoxazole with 20 mg/kg/daytrimethoprim. For parenteral use, the drug is diluted 1:25 in 0.9% saline or 5% dextrosein water and infused over 90-120 min. For oral treatment 1920 mg (two 'doublestrength' tablets) is given three or four times per day.

Parenteral treatment with co-trimoxazole and pentamidine (4 mg/kg od) were equallyefficacious, with approximately 70% of patients surviving, and a correspondingly highincidence of toxicity (Klein et al., 1992). The toxicity of co-trimoxazole can be markedlydiminished if the dosage is reduced to maintain serum trimethoprim concentrations of



5-8 mg/L (without loss of efficacy) (Sattler et al., 1988). In practice this can be achievedby giving 75% of full dosage co-trimoxazole (Sattler et al., 1988). In patients withmoderate or severe PCP, co-trimoxazole is generally given intravenously for the first10-14 days followed by oral therapy for the remainder of the course of treatment. Theoral formulation of co-trimoxazole is well absorbed and patients with mild pneumoniamay be treated as out-patients under the close supervision of a physician.

The majority of unwanted effects caused by co-trimoxazole first become apparentafter 6-14 days of therapy. These include neutropenia and anaemia in up to 40% ofpatients, fever (25%), rash (20%), abnormal liver function (10%) and thrombocyto-penia (5%) (Sattler et al., 1988). The addition of folic or folinic acid neither preventsnor attenuates haematological toxicity (Bygbjerg et al., 1988) and may be associatedwith increased therapeutic failure and mortality (Salfrin, Lee & Sande, 1994), possiblydue to the folinic acid antagonising the blockage of folic acid metabolism in P. cariniiby trimethoprim and sulphamethoxazole. During treatment, full blood count, liverfunction tests and urea and electrolytes should be closely monitored at least twiceweekly.

Several hypotheses have been suggested to account for the increased frequency ofadverse reactions caused by co-trimoxazole in HIV infected individuals with PCP(Koopmans et al., 1995), including those induced by HIV infection such as alterationsof IgE synthesis or glutathione deficiency, and changes of acetylator status dependentmetabolism of co-trimoxazole to toxic metabolites such as hydroxylamines andimmunopathogenic effects induced by HIV and other viruses like EBV and CMV(Koopmans et al., 1995).

Intolerance to co-trimoxazole during treatment is not associated with an increasedrisk of hypersensitivity reactions (Hardy et al., 1992) and desensitisation can besuccessful for some individuals intolerant to the drug (Jung & Paauw, 1994; Bachmeyeret al., 1995).

Pentamidine

Pentamidine (an aromatic diamidine) has broad spectrum anti-protozoal activity; itinhibits metabolism of P amino benzoic acid, interferes with anaerobic glycolysis,inhibits oxidative phosphorylation and impairs nucleic acid and protein synthesis.

Intravenous pentamidine is the second choice for PCP whatever the severity and isgiven at a dosage of 4 mg/kg/day diluted in 250 mL of 5% dextrose in water over 1-2 hfor 21 days (Sattler et al., 1988). When the glomerular filtration rate falls 10-50 mL/minthe drug should be given every 36 h, and when < 10 mL/min it should be administeredevery 48 h (Miller, 1994). Intramuscular administration is no longer recommended aspentamidine can cause sterile abscesses.

Up to 60% of patients have an isolated elevation of serum creatinine; almost halfof patients develop leucopenia, or hypotension (which is less likely if the drug isinfused slowly over 1-2 h); nausea and vomiting occur in up to 25% of patients andhypoglycaemia affects approximately 20% of patients (Sattler et al., 1988). Reducingthe dosage to 3 mg/kg/day leads to lower toxicity without compromising efficacy (Sattleret al., 1988). Consequently, during therapy blood pressure, the full blood count, andserum glucose, calcium and electrolytes should be closely monitored. Combiningintravenous pentamidine with intravenous high dosage co-trimoxazole appears to


P. carina infection 43

confer no therapeutic advantage and the combination has a much higher toxicityprofile than either drug used alone (Haverkos, 1984).

Nebulised pentamidine

Patients with mild or moderate severity PCP responded to 3 mg/kg pentamidine givenintravenously, whereas only half of those given 600 mg od by nebulisation using aRespirgard II nebuliser recovered (Conte et al., 1990).

Patients given nebulised pentamidine at a dosage of 8 mg/kg od respond very slowly,and it may take 10-14 days before fever and dyspnoea begin to resolve and there is anyappreciable improvement in arterial blood gases and radiographic abnormalities(Miller, Godfrey-Faussett & Semple, 1989a). As very little pentamidine is absorbedsystemically, extrapulmonary dissemination may not be suppressed (Coker et al., 1991).There is also a higher relapse rate compared with patients treated with co-trimoxazole.

Consequently, nebulised pentamidine is now rarely used to treat mild or moderatelysevere PCP and it has been suggested that pentamidine should also be given (inconventional doses) parenterally for the first 3-5 days to ensure rapid intrapulmonaryaccumulation of drug and to reduce the likelihood of extrapulmonary pneumocystosis(Miller & O'Doherty, 1995).

Dapsone with trimethoprim

Treatment of mild and moderately severe PCP with 100 mg/kg/day dapsone andtrimethoprim 20 mg/kg/day given orally for 21 days appears to be as effective asco-trimoxazole given orally at a dosage of 120 mg/kg/day (Medina et al., 1990). Thetoxicity of both regimens is similar although dapsone/trimethoprim is better tolerated.Methaemoglobinaemia due to dapsone occurs in most patients, but is rarelysymptomatic, and up to half of patients develop mild hyperkalaemia (5.1-6.1 mmol/L)whilst taking dapsone and trimethoprim.

Dapsone with trimethoprim is useful for treating patients with mild or moderatelysevere PCP who cannot tolerate co-trimoxazole. The recently published AIDS ClinicalTrials Group Study 108, comparing oral regimens of co-trimoxazole 1920 mg tds,dapsone 100 mg od and trimethoprim 300 mg tds or clindamycin 600 mg tds andprimaquine 30 mg od, showed no differences in either time to treatment failure, theoverall treatment failure rate (all were < 10%) or the frequency of dose-limiting toxicity(24-36%) (Hardy et al., 1994).

Clindamycin and primaquine

The combination of the broad spectrum antibiotic clindamycin and the anti-protozoaldrug primaquine is now widely used for treatment of whatever severity although thereis no licence in the UK for this indication. This drug combination was originally usedas 'salvage' therapy for patients with mild to moderately severe PCP who were failingto respond to treatment with co-trimoxazole or pentamidine (Toma et al., 1989);clindamycin was given intravenously. More recent trials have shown the drugs to beeffective when given orally (Hardy et al., 1994; Black, Feinberg & Murphy, 1994).Approximately 60% of patients develop a rash. Methaemoglobinaemia due toprimaquine affects <;40% of patients and is less likely if a dosage of 15 mg od is used



rather than 30 mg od (R. F. Miller, personal observation). Approximately one quarterof patients develop diarrhoea and stool samples should be analysed for the presence ofClostridium difficile toxin.

Atovaquone

The anti protozoal drug atovaquone (an 1,4-hydroxynaphthaquinone) has been usedto treat patients with mild and moderately severe PCP. In a double blind comparison138 of 160 (20%) patients treated with atovaquone 750 mg tds and 10 of 146 (7%) ofthose who received co-trimoxazole 1920 mg tds did not respond to therapy. Within 4weeks of completing treatment there were 11 deaths in the atovaquone group, of whichfour were due to PCP compared to only one death in the co-trimoxazole group. Thecommonest side-effects of atovaquone therapy were nausea, vomiting, constipation andrash. In another open randomised trial of mild or moderately severe PCP, treatmentwas successful in 32 of 56 (67%) who received atovaquone 750 mg tds orally and in only21 of 53 (40%) of those received pentamidine 3-4 mg od iv. Therapy was discontinuedbecause of adverse events in 19 (36%) of those treated with pentamidine and 2 patients(4%) given atovaquone (Dohn et al., 1994).

Tablets of atovaquone are variably absorbed and should be taken with food. Thisis important as, in Hughes' study, patients who had diarrhoea at entry to the study hadlower plasma drug concentrations after atovaquone, a higher failure rate and greaterrisk of death than did those given co-trimoxazole (Hughes et al., 1993). A suspensionof the drags offers increased bioavailability and may provide effective alternative oraltherapy to currently available regimens, but it remains to be seen whether the lowtoxicity profile is maintained with increased absorption of drug.

Trimetrexate

The methotrexate analogue, trimetrexate, is an inhibitor of dihydrofolate reductase, andin vitro it is 1500 times more potent than trimethoprim (Allegra et al., 1987ft). P. cariniilacks a folate membrane transport system and so cannot take up classical folatestructures. Folinic acid is therefore co-administered with trimetrexate to protect humancells from drug toxicity. With moderate and severe P. carinii pneumonia (Sattler et al.,1994) trimetrexate 45 mg/m2 od iv and folinic acid 20/m2 qds, was less effective thanco-trimoxazole 120 mg/kg/day with, treatment failure rates at 21 days of therapy of38% and 20% respectively (Sattler et al., 1994). In addition, a greater number ofpatients treated with co-trimoxazole survived. In contrast to previous studies (Masur,1992), there was no evidence of a high relapse rate following trimetrexate/folinic acidtherapy. Overall, adverse events were similar for both regimens but serious treatmentlimiting haematological toxicity occurred less frequently after trimetrexate/folinic acid(Sattler et al., 1994). Thus, trimetrexate/folinic acid may be beneficial in patients withmoderate or severe PCP when first line therapy has failed. Its role as 'salvage' therapyhas also been demonstrated (Allegra et al., 1987a) as 11 of 16 (69%) patients intolerantof, or failing to respond to intravenous co-trimoxazole and pentamidine achieved aresponse to pentamidine trimetrexate (at the lower dosage than above—30 mg/m2 od)and folinic acid (20 mg/m2 qds) (Allegra et al., 1987a). As yet, trimetrexate is notlicensed in the UK.



Efiornithine

Eflornithine (or a-difluromethylornithine—DFMO) is an inhibitor of polyaminesynthesis and has been used as salvage therapy for small numbers of patients with PCP.When eflornithine 400 mg/kg/day was given in divided doses for 14 days to patientsfailing to respond to co-trimoxazole or pentamidine, 21 of 31 (68%) responded (Smithet al., 1990). There was evidence of bone marrow suppression in 48% of cases and thiswas severe enough to discontinue treatment in 16% of cases; infusion site phlebitisoccurred in 52% of cases. In another open label prospective study of patients with PCPof all grades of severity, 39% of those given eflornithine (400 mg/kg/day) and 40% ofthose treated with co-trimoxazole (120 mg/kg/day) successfully completed therapy(Smith et al., 1992). All patients who stopped eflornithine did so because of failurerather than drug related side-effects, whereas the reverse was true of co-trimoxazole.Thus, eflornithine should not be used as first line therapy for PCP and should bereserved for 'salvage' therapy. Eflornithine is not licensed in the UK.

Corticosteroids

The role of adjuvant therapy with high dose corticosteroids for patients with moderateor severe PCP is now clearly established as treatment reduces both the risk of respiratoryfailure (by up to 50%) (Bozzette et al., 1990), and the risk of death (by up to 33%)(Gagnon et al., 1990). Oral or intravenous corticosteroids should be started at the sametime, or within 72 h of commencing specific anti-pneumocystis therapy when patientshave a PaO2 <. 4.7 kPa (National Institutes of Health, 1990). The mechanism by whichsteroids act is unclear but it may be by reducing the body's own intrapulmonaryinflammatory response to P. carinii. If this hypothesis is correct, corticosteroids shouldbe given early in treatment. There are no data from prospective studies to support theuse of glucorticoids in the treatment of mild disease. However, it would be difficult toshow benefit as antimicrobial treatment is so effective in this sub group of patients.

Several regimens have been used although no corticosteroids are licensed for thetreatment of PCP. The commonly used regimen is oral prednisolone 40 mg bd for 5days, followed by 40 mg od on days 6-10, then 20 mg od on days 11-21 (NationalInstitutes of Health, 1990). Methylprednisolone can be given iv at 75% of these dosesor as 1 g on days 1-3 and 0.5 g on days 4 to 6, followed by oral prednisolone, initially40 mg tailing off over 10 days (Miller & Mitchell, 1992). Alternatively, hydrocortisoneis sometimes given iv in a dose of 200 mg qds daily for 5 days (Miller, 1994).

Management of PCP

Patients with mild disease can be treated orally with co-trimoxazole as out-patients ifthey are willing to attend the out-patient clinic for regular review, able to cope at home,and there is clinical and radiographic evidence of recovery. If, despite clinical recovery,oral treatment is not tolerated, the drug can be given iv or treatment can be changedto oral dapsone with trimethoprim, or oral clindamycin with primaquine. Oralatovaquone, in tablet formulation, would be the third choice of treatment.

Patients with moderate and severe PCP should always be managed initially in hospitalwith either co-trimoxazole iv or pentamidine iv together with adjuvant corticosteroidtherapy. If patients fail to respond to either regimen within 7-10 days then, where



feasible, treatment should be switched to the other drug, allowing at least 48 h overlapfor intrapulmonary accumulation of the new drug to occur (Miller, 1994). However,such patients have a very poor outcome (Wharton et al., 1986). Patients with moderateand severe PCP who still do not respond should be treated with clindamycin iv withoral primaquine, or intravenous trimetrexate with folinic acid. Eflornithine is a thirdchoice.

Prognosis of P. carinii pneumonia

Several clinical and laboratory features have been identified as having prognosticsignificance (Table III). In a prospective study, a PCP severity score was constructedbased on serum lactate dehydrogenase enzyme levels, the alveolar-arterial oxygengradient and the percentage of neutrophils in bronchoalveolar lavage fluid, and thiswas shown to have high prognostic significance—with the highest scores indicating thepoorest outcome (Speich et al., 1992).

The deteriorating HIV infected patient with P. carinii pneumonia

Before considering a switch of therapy, when faced with a patient with PCP who isdeteriorating despite specific therapy, it is important to remember that this may be dueto severe progressive PCP, side-effects of treatment or other causes such as pulmonaryKaposi's sarcoma, bacterial pneumonia mimicking PCP, co-infections, or other(iatrogenic) complications (pneumothorax, left ventricular failure or anaemia). Theclinician should consider treating any pathogen present in sputum or lavage fluid andconsider repeating bronchoscopy or proceeding to open lung biopsy in order to confirmthe diagnosis is correct (Miller & Mitchell, 1990).

Table III. Prognostic factors predictive of a poor outcome in HIV patients with P. cariniipneumonia (cf. Jeffrey el al., 1993)

On admissionNo previous knowledge of HIV statusRecurrent P. carinii pneumonia (second, third or fourth episode)Prolonged history of dry cough/dyspnoea (> 4 weeks)Tachypnoea (>30/min)Poor oxygenation PaO2 < 7.0 kPa

alveolar-arterial oxygen gradient ;>4.0 kPaMarked chest radiographic abnormalities

diffuse bilateral interstitial infiltrateswith or without alveolar consolidation

Peripheral blood leucocytosis (>10.8 x 10»/L)Low serum albumin (<35g/L)Raised serum lactate dehydrogenase enzyme levels (>300 IU/L)

Following admissionBacterial co-pathogen in induced sputum or bronchoalveolar lavage fluidNeutrophilia (>5%) in bronchoalveolar lavage fluidMarked interstititial oedema in transbronchial biopsy specimensSerum lactate dehydrogenase enzyme levels that remain elevated despite specific anti-/\ carinii

therapy



General measures in a deteriorating patient

Pulmonary oedema and fluid overload may complicate severe PCP. ECG evidence ofmyocardial ischaemia is found in many severely ill hypoxaemic patients with PCP andmay lead to reduced left ventricular compliance and increased left atrial pressure withdevelopment of pulmonary oedema (Jeffrey, Bullen & Miller, 1993). There is oftenconcomitant diminished renal sodium excretion. As the large volumes of fluid requiredto administer co-trimoxazole may produce fluid overload and left ventricular failure,the diluent may need to be changed from 0.9% saline to 5% dextrose in water and thedilution ratio reduced to 1:10.

All patients with PCP who are hypoxaemic should receive supplementary oxygentherapy with the aim of maintaining the PaO2 ^ 8.0 kPa (or the arterial oxygensaturation (SaO2) ;> 90%). Once an inspired oxygen concentration of 60% (deliveredby a standard Venturi principle face mask) is needed to maintain a PaO2 ;> 8.0 kPa,alternative ventilatory support should be considered, such as non-invasive ventilatorysupport with nasal or face mask Continuous Positive Airways Pressure (CPAP) (Miller& Semple, 1991). This can 'buy' time for specific P. carinii therapies to work. Themechanism by which CPAP works is unclear but is probably acting as a pneumatic'splint' holding open narrow, poorly compliant airways thus improving oxygenation.CPAP is well tolerated by patients who often report a significant reduction in dyspnoeaand is particularly useful when a patient deteriorates following bronchoscopy. Once apneumothorax has been excluded as a cause for deterioration, CPAP will frequently tidethe patient over this self limiting episode. Pneumothorax and mediastinal emphysema,gastric aspiration and mask pressure necrosis are rare complications of CPAP (Miller& Semple, 1991).

If CPAP ventilation fails to maintain adequate oxygenation, or the patientbecomes tired, or the PaCO2 rises, then intubation and mechanical ventilation shouldbe considered. Most centres would advocate mechanical ventilation for a firstepisode of PCP and for severe deterioration occurring post-bronchoscopy (Miller& Mitchell, 1990). A recent study of HIV infected patients with severe PCP andrespiratory failure who were mechanically ventilated showed that the intervalbetween the start of specific anti P. carinii therapy and the need for mechanicalventilation, as well as the duration of HIV seropositivity, were the only two factorswhich discriminated between survivors and non-survivors. The mortality rate was50% in patients who received < 5 days of co-trimoxazole and corticosteroids and 95%in those receiving >5 days of therapy; survivors had a shorter HIV history(Staikowsky et al., 1993). Thus, it appears that HIV-infected patients with PCPand respiratory failure who require mechanical ventilation have a poor prognosis.However, adjuvant glucocorticoids use may have influenced the natural history ofP. cann/Y-associated respiratory failure by selecting out a subgroup of patientswith severe pneumonia in whom treatment has failed. Before deciding to instituteventilation it is important to carefully consider the patient's previous HIV historyand current quality of life, their likely prognosis, not only from the episode ofpneumonia but also in the long term from HIV disease, and to take into accountthe wishes of the patient and their partner or next of kin (Miller & Mitchell, 1990).Once a patient has been ventilated, it is important to set clear goals and objectivesso that the patient will not remain mechanically ventilated with an ever-decreasingchance of recovery.


48

Table IV.

First lineSecond line

Third line

Fourth lineFifth line

Adjuvantsteriods

R.

Treatment of P. carinii

Mild

co-trimoxazoleiv pentamidine

or clindamycin andpnmaquine

or dapsone andtrimethoprimatovaquone

trimetrexatenebulised pentamidine

eflornithineunproven

benefit

F. Miller et at.

pneumonia and according

Moderate


or dapsone andtrimethoprim

clindamycin andprimaquine ortrimetrexate or

atovaquoneeflornithine

b

benefit

to disease severity*

Severe


clindamycin andprimaquine ortrimetrexate

eflornithine

benefit

•Notes: (i) For doses and route of administration see text; (ii) co-trimoxazole is the best treatment for P.carinii pneumonia of any severity; if use cotnmoxazole then stop zidovudine; (iii) Avoid co-trimoxazole,dapsone and pnmaquine in patients with glucose-6-phosphate dehydrogenase deficiency.

bIf used combine with iv pentamidine for the first 3—5 days of therapy.

Conclusion

Application of molecular biological techniques has shown that P. carinii is a fungus andnot a protozoan. Clinical infection in the immunosuppressed human host is not azoonosis and arises by reinfection, from an environmental source, rather than byreactivation. The diagnosis of PCP in most cases is made by invasive tests such asfibreoptic bronchoscopy with bronchoalveolar lavage or sputum induction. Insusceptible HIV infected patients primary and secondary prophylaxis should be given.The first choice is oral co-trimoxazole 960 mg od or three times a week; nebulisedpentamidine or dapsone with pyrimethamine are suitable alternatives in patients whoare intolerant of co-trimoxazole. In a patient with acute PCP it is important to makean assessment of disease severity (based on clinical, radiographic, and blood gas criteria)in order to identify those who will benefit from adjuvant glucocorticoids. First choicetherapy for PCP of all degrees of severity is co-trimoxazole (Table IV); in moderate tosevere disease adjuvant steroids should also be given. In patients failing to respond toco-trimoxazole or who are hypersensitive to it, iv pentamidine is second line therapyin those with severe disease and iv pentamidine, oral dapsone with trimethoprim, or oralclindamycin with primaquine are suitable alternatives in those with mild or moderatelysevere disease.

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pneumocystis carinii infection: current treatment and prevention

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