Pneumonia, atovaquone treatment

Atovaquone, a hydroxynaphthoquinone (Figure 52-2), was initially developed as an antimalarial agent, and as a component of Malarone is recommended for treatment and prevention of malaria. Atovaquone has also been approved by the FDA for the treatment of mild to moderate P jiroveci pneumonia. 

Clinical Use. Atovaquone (Mepron) is used primarily to treat the protozoon that causes toxoplasmosis and the fungus that causes pneumocystis pneumonia in immunocompromised patients.6 This drug is not typically the primary treatment for pneumocystis, but is often reserved for patients who cannot tolerate more traditional treatments using sulfamethoxazole and trimethoprim (see Chapter 34) or pentamidine (see later). Atovaquone can also be used to prevent and treat resistant cases of malaria, and the antimalarial effects of this drug seem especially useful when combined with proguanil.48... 

Two other agents show promise in treatment of ocular toxoplasmosis. Atovaquone, primarily used for mild to moderate episodes of Pneumocystis carinii pneumonia, has been effective in small series of patients with toxoplasmosis. It appears to have activity against both tachy-zoites and tissue cysts. More recent studies on atovaquone in toxoplasmosis are limited to murine models, and no further reports on this drug therapy in humans have been published. Azithromycin, a macrolide antibiotic, is efficacious against T. gondii and can also kill tissue cysts. A randomized study of 46 patients compared the combinations of azithromycin plus pyrimethamine versus pyrimethamine plus sulfadiazine in treatment of ocular toxoplasmosis efficacy was similar, but the azithromycin/ pyrimethamine regimen caused less adverse effects. 

Atovaquone 250 mg tds has been compared with co-tri-moxazole 320/1600 mg/day for 21 days in the treatment of P. jiroveci pneumonia in 408 patients. Therapeutic efficacy was similar, but atovaquone was much better tolerated, with a far lower incidence of rash, liver dysfunction, fever, nausea, and pruritus, and no neutropenia, chills, headache, renal impairment, or thrombocytopenia (1). However, pre-existing diarrhea was associated with an increased mortality in the atovaquone group. 

When atovaquone was compared with intravenous pentamidine in the treatment of mild and moderate Pneumocystis jiroveci pneumonia in an open trial, the success rates were similar. However, withdrawal of the original treatment was much more frequent with pentamidine (36%) than atovaquone (4%) (4). However, the authors conclusion that the two approaches have a similar success rate has been challenged, and their series was small (5,6). Treatment-limited adverse effects occurred in only 7% of patients given atovaquone, compared with 41 % given pentamidine. They included cases of rash and an increase in creatinine concentrations atovaquone (unlike pentamidine) produced no vomiting, nausea, hypotension, leukopenia, acute renal insufficiency, or electrocardiographic abnormalities, but it did cause one case of dementia (4). 

Atovaquone suspension (750 mg bd n — 34) or tablets (750 mg tds n — 20) have been retrospectively compared in the treatment of P. jiroveci pneumonia in HIV-positive... 

Hughes WT, LaFon SW, Scott JD, Masur H. Adverse events associated with trimethoprim-sulfamethoxazole and atovaquone during the treatment of AIDS-related Pneumocystis carinii pneumonia. J Infect Dis 1995 171(5) 1295-301. 

Rosenberg DM, McCarthy W, Slavinsky J, Chan CK, Montaner J, Braun J, Dohn MN, Caldwell PT. Atovaquone suspension for treatment of Pneumocystis carinii pneumonia in HIV-infected patients. AIDS 2001 15(2) 211-14. 

Immunosuppressed radiation victims may also be at risk for reactivation of cytomegalovirus (CMV) and Pneumocystis carinii pneumonia. In a limited casualty situation, if resources are available, clinicians should obtain CMV serology. In addition, patients should have a sensitive assay (antigen assessment or polymerase chain reaction test) every 2 weeks for 30 days postexposure, while those with documented previous CMV exposure should have the assay repeated until 100 days postexposure (2). Patients developing lymphopenia should have a CD4 cell count considered at 30 days postexposure. Those with a CD4 count below 0.2000 x 10 cells L" are at risk for Pneumocystis carinii pneumonia. Physicians should withhold trimethoprim-suha prophylaxis until the leukocyte count is above 3.0 x 10 cells L" or until the absolute neutrophil count is above 1.5 x 10 cells L . Atovaquone, dap-sone and aerosohzed pentamidine are alternative prophylactic agents. Patients should continue prophylactic treatment until the CD4 count reaches or exceeds 0.2000 X 10 cells L, which may occur over several months (2). 

The incidence of Pneumocystis carinii pneumonia (PCP) within the first year after transplantation is reported to be 3% to 5%. " Low-dose trimethoprim-sulfamethoxazole (TMP-SMX 400 mg/ 80 mg three times weekly) is effective in the prevention of PCP infections. Alternative agents include aerosolized pentamidine (300 mg every month), dapsone, and atovaquone. The duration of PCP prophylaxis is unclear. The risk of infection caused by P. carinii is likely to decrease as immunosuppression is reduced therefore, prophylaxis in patients requiring treatment for acute rejection may be appropriate. 

Atovaquone is an antiprolozoal agent (750 mg p.o. t.i.d for 21 days), that inhibits mitochondrial electron transport in metabohc enzymes of microorganisms. This may cause inhibition of nucleic acid and adenosine triphosphate synthesis. Atovaquone is indicated in the treatment of mild to moderate Pneumocystis carinii pneumonia in patients who cannot tolerate trimethoprimsulfamethoxazole, and in acute oral treatment of mild to moderate PCP in patients who are intolerant to trimethoprimsulfamethoxazole. 

Atovaquone (mepron) has potent activity against Plasmodium species and the opportunistic pathogens Pneumocystis jirovici arul Toxoplasma gondii it is FDA approved for treatment of P. jirovici pneumonia in patients intolerant of trimethoprim-sulfamethoxazole. In patients with uncomplicated P. falciparum malaria, combination therapy with proguanil and atovaquone evoked high cure rates with few relapses and minimal toxicity. A fixed combination of atovaquone with proguanil (maiarone) is available in the U.S.for malaria prophylaxis and treatment. 

When the CD4 count of this patient fell below 200/pL. prophylaxis against pneumocystis pneumonia was instituted. The currently recommended therapy is double-strength trimethoprim-sulfamethoxazole or dapsone. Alternative prophylactic regimens include aerosolic pentamidine, dapsone plus pyrimethamine, and atovaquone. Primary prophylaxis against toxoplasmosis is normally recommended with CD4 cell counts below 100/pL in AIDS patients who are IgG antibody-positive. Trimethoprim-sulfamethoxazole plus dapsone is also prophylactic against toxoplasmosis. With the continued decline in CD4 cells, exacerbation of candidal infection may occur despite use of clotrimazole troches, necessitating treatment with fluconazole or itraconazole. 

It must be said that how such information gets disseminated is controversial in the USA. A good recent example is an investigation of atovaquone vs. i.v. pentamidine in the treatment of mild to moderate Pneumocystis carinii pneumonia. This report included a decision tree to estimate the costs and cost-effectiveness of atovaquone vs. Pentamidine for cotrimoxazole-intolerant patients (Zarkin et al 1996). Clinical outcomes were based on data from a previous randomized controlled trial (RCT) (Phase III) comparing the two medications, while economic outcomes were based on... 

Zarkin GA, Bala MV, Wood LL et al (1996) Estimating the cost effectiveness of atovaquone versus intravenous pentamidine in the treatment of mild to moderate pneumocystis pneumonia. Pharmacoeconomics 6 525-34. 

Established interactions of clinical importance. Atovaquone suspension used for the treatment or prevention of Pneumocystis pneumonia must be taken with food, since this is likely to increase the likelihood of successful treatment and survival. Alternatively, an enteral nutritional supplement with a high-fat content appears to be suitable. In the US, the manufacturer says that, for patients who have difficulty taking atovaquone suspension with food, parenteral therapy for Pneumocystis pneumonia should be considered. ... 

Trimethoprim-sulfamethoxazole (TMP-SMX) (20 mg/kg/day of trimethoprim) is the treatment of choice for P. carinii pneumonia (PCP). Oral therapy with TMP-SMX is reserved for children with mild PCP who do not have malabsorption or diarrhea. Intravenous pentamidine (4 mg/kg/day, given once a day) can be given to children with PCP who are intolerant of TMP-SMX or who have not responded after 5 days of TMP-SMX therapy. Other treatment regimens that may be considered for patients who are intolerant of or fail TMP-SMX and pentimidine are (1) atovaquone (40 mg/kg/ day, in two divided doses) for mild/moderate PCP only (2) dapsone with trimethoprim (3) trimetrexate with leucovorin and (4) clindamycin and primaquine. These alternate treatments have limited experience in pediatric patients. 

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