TREATMENT P. jirovecii Pneumonia
The treatment of choice for PCP is trimethoprim-sulfamethoxazole (TMP-SMX), given either IV or PO for 14 days to non-HIV-infected patients with mild disease and for 21 days to all other patients (Table 215-1). TMP-SMX, which interferes with the organism’s folate metabolism, is at least as effective as alternative agents and is better tolerated. TMP-SMX can cause leukopenia, hepatitis, rash, and fever as well as anaphylactic and anaphylactoid reactions, and patients with HIV infection have an unusually high incidence of hypersensitivity to TMP-SMX. Monitoring of serum drug levels is useful if renal function or toxicities are issues. Maintenance of a 2-h post-dose serum sulfamethoxazole level of 100–150 μg/mL has been associated with a successful outcome. Resistance to TMP-SMX cannot be measured by organism growth inhibition in the laboratory because Pneumocystis cannot be cultured. However, mutations in the target gene for sulfamethoxazole that confer in vitro sulfa resistance to other organisms have been found in Pneumocystis. The clinical relevance of these mutations for the response to therapy is unknown. Sulfadiazine plus pyrimethamine, an oral regimen more often used for treatment of toxoplasmosis, also is highly effective. Dapsone plus pyrimethamine or dapsone plus trimethoprim also can be used.
Intravenous pentamidine or the combination of clindamycin plus primaquine is an option for patients who cannot tolerate TMP-SMX and for patients in whose treatment TMP-SMX appears to be failing. Pentamidine must be given IV over at least 60 min to avoid potentially lethal hypotension. Adverse effects can be severe and irreversible and include renal dysfunction, dysglycemia (life-threatening hypoglycemia that can occur days or weeks after initial infusion and be followed by hyperglycemia), neutropenia, and torsades des pointes. Clindamycin plus primaquine is effective, but primaquine can be given only by the oral route—a disadvantage for patients who cannot ingest or absorb oral drugs. Oral atovaquone is also a reasonable option for patients with mild disease who have no impediments to absorbing an oral drug that requires a high-fat meal for optimal absorption.
A major advance in therapy for PCP was the recognition that glucocorticoids could improve survival rates among HIV-infected patients with moderate to severe disease (room air PO2, <70 mmHg; or alveolar–arterial oxygen gradient, ≥35 mmHg). Glucocorticoids appear to reduce the pulmonary inflammation that occurs after specific therapy is started and organisms begin to die, eliciting inflammation. Therapy with glucocorticoids should be the standard of care for patients with HIV infection and probably is also effective for patients with other immunodeficiencies. This treatment should be started for moderate or severe disease when therapy for PCP is initiated, even if the diagnosis has not yet been confirmed. If HIV-infected or HIV-uninfected patients are receiving high-dose glucocorticoids when they develop PCP, there are theoretical advantages to either increasing the steroid dose (to reduce the inflammatory response to the dying organisms) or decreasing the steroid dose (to improve immune function), but there is no convincing evidence on which to base any specific strategy.
No definitive trials have defined the best therapeutic algorithm for patients in whom TMP-SMX treatment for PCP is failing. If no other treatable infectious or noninfectious processes are detected and pulmonary dysfunction appears to be due to PCP alone, many authorities would switch from TMP-SMX to either IV pentamidine or IV clindamycin plus oral primaquine. Some authorities would add the second drug or drug combination to TMP-SMX rather than switching regimens. If patients are not already receiving them, glucocorticoids should be added to the regimen; the dosage and regimen, which are usually chosen empirically, depend on what glucocorticoid regimen (if any) the patient was receiving when PCP therapy was begun.
For patients with HIV infection who present with PCP before the initiation of ART, ART should be started within the first 2 weeks of therapy for PCP in most situations. Immune reconstitution inflammatory syndrome (IRIS) can occur, however, and the decision to initiate ART thus requires considerable expertise in optimal timing relative to PCP recovery as well as in the other factors that are relevant when ART is initiated in any patient.