Treating PCP<4>

Klein (1992) treated 160 patients with PCP with intravenous co-trimoxazole (TMP 20 mg/kg/day plus SMX 100 mg/kg/day, 92 patients) or intravenous pentamidine (4 mg/kg/day, 68 patients) for 21 days. 39 (42%) of the co-trimoxazole required change of therapy because of failure to respond, plus a further 31 (34%) due to drug toxicity. This compared to 27 (40%) and 17 (25%) of the pentamidine group, respectively. Overall survival rates were similar (67% (62/92) initially receiving co-trimoxazole; 74% (50/68) initially receiving pentamidine). For patients requiring a change of therapy due to failure to respond, survival rates were 46% (18/39) for co-trimoxazole and 56% (15/27) for pentamidine. For those requiring change of therapy due to toxicity, survival rates were 97% (30/31) for co-trimoxazole and 94% (16/17) for pentamidine.

Sattler (1988) treated 70 people with PCP with either co-trimoxazole or intravenous pentamidine. Co-trimoxazole recipients experienced better clinical responses and 86% survived, versus 61% of pentamidine recipients. Dose modifications were required in 25 of 36 co-trimoxazole recipients, and 8 of 34 pentamidine recipients.

Sattler (1994) (ACTG 029/031) conducted a double-blind randomized study comparing trimetrexate (45 mg/m² once daily) plus folinic acid (20 mg/m² every 6 hours) versus co-trimoxazole as first-line treatment for moderate-to-severe PCP in 215 AIDS patients. At assessment at day 21, 20% of co-trimoxazole and 38% of trimetrexate recipients were classed as clinical failures. Failure rates due to lack of efficacy were 24% for co-trimoxazole recipients and 40% in the trimetrexate group. At day 56 a higher proportion of trimetrexate recipients than co-trimoxazole recipients had died (31% versus 16%). Serious side effects were less common in the trimetrexate group.

Medina (1990) randomised 60 patients with AIDS and mild to moderately-severe PCP to receive either trimethoprim/dapsone (20 mg/day and 100 mg/day by mouth respectively) or co-trimoxazole (120 mg/kg/day by mouth respectively). No patients received concomitant AZT. The regimens were equally effective, with 2/30 patients in the trimethoprim/dapsone group failing, and 3/30 in the co-trimoxazole group failing. Co-trimoxazole was associated with significantly greater toxicity: 9/30 patients who received trimethoprim/dapsone and 17/30 who received co-trimoxazole had a major adverse reaction requiring a switch to intravenous pentamidine. The most frequent toxicity in the trimethoprim/dapsone arm was rash; in the co-trimoxazole group elevated LFT, neutropenia and rash were most frequently observed.

Safrin (1996) reported the results of ACTG 108, a trial that enrolled 181 people with mild-to-moderate PCP. It compared treatment with either co-trimoxazole (2 double-strength tablets every 8 hours), dapsone (100 mg/day) plus trimethoprim (300mg every 8 hours), or clindamycin (600mg every 8 hours) plus primaquine (30 mg/day). 50%-59% of participants successfully completed 14-21 days of their randomized therapy. No significant differences in therapeutic failure rate were seen among the 3 therapies (9.4% co-trimoxazole, 11.9% dapsone-trimethoprim, 6.9% clindamycin-primaquine). Dose-limiting toxicity was lowest with dapsone-trimethoprim (24%) compared with co-trimoxazole (36%) or clindamycin-primaquine (33%), but not significantly different.

Toma (1998) investigated clindamycin with primaquine as an alternative treatment for PCP. 45 received 450mg clindamycin four times daily and primaquine, and 42 people received standard doses of TMP-SMZ. Success was reported in 76% of the clindamycin group in comparison to 79% of the TMP-SMZ group. The clindamycin group experienced fewer adverse events, less steroid use and more rashes.

Feinberg (1992) evaluated the results of an expanded-access program which provided trimetrexate to 752 people unable to take co-trimoxazole and intravenous pentamidine. 34% of participants were classified as responders.

Hughes (1993) enrolled 322 participants with AIDS in a Phase III randomized, double-blind trial comparing atovaquone (750mg three times a day) with co-trimoxazole (320mg TMP/1600mg SMX three times a day) for the treatment of mild to moderate PCP. Therapy was successful in 99/160 (62%) patients randomized to atovaquone and 103/162 (64%) patients randomized to co-trimoxazole. More patients in the atovaquone group failed due to lack of response, while more patients in the co-trimoxazole group failed due to drug toxicity (20% of atovaquone recipients and 7% of co-trimoxazole recipients discontinued due to inadequate response, while 7% of atovaquone recipients and 20% of co-trimoxazole recipients discontinued due to drug toxicity). Toxicities included rash, liver function abnormalities, vomiting and fever. Mortality within four weeks of the completion of treatment was higher in the atovaquone group (11 patients) than in the co-trimoxazole group (1 patient).

Dohn (1994) compared atovaquone (750mg orally three times a day) with pentamidine (3-4 mg/kg/day intravenously) as primary or salvage therapy in patients with mild or moderate PCP. Overall, the two treatments had similar rates for successful treatment, as pentamidine had more dose-limiting toxicity and atovaquone had a higher rate of treatment failure. Among 56 patients with primary PCP randomized to receive atovaquone, 57% were treated successfully, 29% had no response, and 4% had a dose-limiting side-effect. Among 53 patients randomized to pentamidine, 40% responded, 17% had no response and 36% had treatment-limiting side-effects. Mortality was equivalent in the two groups.

Montgomery (1995) enrolled 367 patients in a randomised, double-blind trial comparing co-trimoxazole (15/75 mg/kg/day intravenously then orally) versus aerosolised pentamidine (AP, 600 mg daily) for treatment of acute PCP. Adverse reactions (rash, elevated liver-enzyme levels, fever, neutropenia, and nausea) occurred more frequently in the co-trimoxazole group. Use of AP was associated with a slower clinical response, and was most effective against mild to moderate PCP. Investigators also noted that the risk of pneumothorax and extrapulmonary PCP appears to be greater with AP than with co-trimoxazole.

Sahai (1989) reported on the use of eflornithine on a compassionate basis in AIDS patients with PCP who were intolerant of or unresponsive to traditional agents. The drug has since been withdrawn by its manufacturer, Merrel-Dow Pharmaceuticals, because of lack of effectiveness.

Experimental treatments

Petty (1999) conducted a safety and dosing study of WR 6026, a drug that has shown activity against PCP in vitro and in animal studies. 49 participants were started at 30mg. Dosage was escalated to between 60mg and 150mg daily. Three of 6 people on the 150mg dose developed methemoglobin. Three others developed rash and two people had triglyceride levels rise above 1000mg/dl.

Resistance

Kazanjian (2001) studied the P. carinii cytochrome b genes from 60 AIDS patients with PCP. 15 patients who had taken atovaquone prophylaxis were matched with 45 patients who had not. Cytochrome b coenzyme Q binding site mutations were found in 8/60 (13%) of all patients. The mutations were observed in 33% of isolates from patients exposed to atovaquone compared with 6% who were not (p = 0.018). Mutations did not affect survival.

Martin (2000) conducted a cross-sectional study of resistance to co-trimoxazole (TMP-SMX) among 7 common bacteria isolates and staphylococcus at the San Francisco General Hospital between 1988-1995. Nearly 40,000 specimens were tested. Incidence of resistance rose from 7.2% in 1988 to 20.4% in 1995, coinciding with the uptake of TMP-SMX prophylaxis. Amongst HIV-infected individuals, resistance rose from 6.3% to 53%: staphylococcus resistance rose from 0 to 48%, e.coli 24% to 74% and Klebsiella 0 to 36%. Resistance to other antibiotics also increased over time. Martin and colleagues concluded that TMP-SMX could not be used for bacterial infections among HIV-infected individuals in San Francisco.

Ma (1999) reported that mutations occurred in the pneumocystis carinii gene targeted by the sulphur component of the treatment. Thus resistance to sulfamethoxazole and dapsone is occurring. There was no evidence of mutations in the gene targeted by the trimethoprim.

Kazanjian (2000) studied 97 people with PCP. 28/37 (76%) who had received sulphur prophylaxis had resistance mutations compared with 14/60 (23%) of those who had not. Mutations were associated with risk of sulphur drug failure, but not with failure of other treatments.

Helweg-Larsen (1999) studied bronchalveolar samples from 144 people (152 episodes) with PCP. Sulphur drug resistance occurred 31 people (20%) with mutations at dihydropteroate synthase (DHPS). Resistance was associated with greater risk of death. DHPS mutations were more common in people who had previously taken sulphur drugs (18/29 or 62%) than in people with no exposure (10%). Mutations were also more likely in people who had taken PCP prophylaxis.

Wininger (2002) conducted a retrospective chart review of the impact of constant prophylactic use of co-trimoxazole on the ecology and the antimicrobial susceptibilities of bloodstream pathogens in 89 people with advanced HIV infection. 124 episodes of bacteraemia occurred with 156 different pathogens. Staphylococcus aureus and Enterobacteriaceae were less common among patients receiving cotrimoxazole prophylaxis. 75% of isolates from treated patients were drug resistant compared 33% of isolates from untreated patients (p<0.001).

Mei (2000) found that P carinii organisations can contain genetic sequences which confer resistance to the sulphur component of co-trimoxazole.

Adjunctive steroids

Adjunctive corticosteroid administration (added to co-trimoxazole or intravenous pentamidine), when initiated at the beginning of treatment, has been demonstrated to decrease the potentially life-threatening inflammatory response and respiratory distress associated with moderate-to-severe PCP. A consensus conference convened by the NIAID to review the results of 5 separate studies determined that early adjunctive steroid therapy reduces the likelihood of death, respiratory failure and deterioration in moderate-to-severe PCP when adjunctive therapy is initiated as early as possible. Prednisolone 50-80mg daily is given by mouth for 5 days, and then continued at a lower dose for 16 days. Corticosteroid treatment should be commenced at the same time as anti-PCP treatment and certainly no later than 3 days after commencing anti-PCP treatment.

Caumes (1994) reported that in a non-randomized retrospective chart review, corticosteroid use was associated with a reduced incidence of adverse skin reactions to co-trimoxazole in AIDS patients receiving treatment for acute PCP. 38 patients in the review received co-trimoxazole alone, and 23 received co-trimoxazole plus corticosteroids for hypoxemia. Rashes occurred in 18/38 (47%) patients receiving co-trimoxazole alone and 3/23 (13%) receiving co-trimoxazole and corticosteroids. A significantly higher rate of mucocutaneous herpes simplex infections was observed in the patients receiving corticosteroids.

Nelson (1993) reported that corticosteroids may increase the risk of clinical CMV disease in patients with CD4 counts below 50. Jensen found that among 148 consecutive patients with a first episode of PCP, those who had CMV cultured from broncho-alveolar lavage fluid had a two times higher mortality within three months from bronchoscopy if they received concomitant steroids, compared with patients who did not receive steroids.

Keating (1994) randomized 60 people with mild PCP to receive standard anti-PCP therapy plus either steroids or an inactive placebo. After 6 months follow-up there was no difference in survival between the groups (73% survival in the steroid group compared with 75% in the placebo recipients). People treated with steroids were not at increased risk of developing CMV retinitis, although they were more prone to bacterial and fungal infections. The researchers conclude that people with mild PCP should receive standard anti-PCP therapy without additional steroids.