Drug Treatment for Pneumocystis Pneumonia

Pneumocystis jiroveci (previously P. carinii) is an atypical opportunistic fungal pathogen that causes pneumonia in immunocompromised individuals.
Pneumocystis pneumonia (PCP) most frequently occurs in HIV-infected patients. It typically develops when the CD4 T-cell count falls below 200 cells/mm³ and is considered an AIDS-defining illness.¹ PCP was one of the leading causes of mortality among HIV patients in the 1980s² but the incidence has fallen since the introduction of highly active antiretroviral therapy (HAART) and the widespread use of PCP prophylaxis. PCP may also occur in patients with primary immune deficiencies, malignancy and those taking prolonged courses of high dose corticosteroids and immunosuppressive therapy after organ transplantation.³ PCP carries a mortality rate of 10-20% in HIV patients and approximately 40% in other immunocompromised individuals.⁴

Co-trimoxazole (trimethoprim and sulfamethoxazole)

Bacteria are obligate folic acid synthesisers (i.e. they rely on the synthesis of folic acid to survive) whereas humans are able to obtain folate through dietary sources.⁵ Trimethoprim and sulfamethoxazole inhibit dihydrofolate reductase and dihydropteroate synthetase respectively and so provide sequential blockade of the folate synthetic pathway and prevent nucleotide synthesis.⁶ The combination of trimethoprim and sulfamethoxazole allows the use of much lower doses of individual drugs and may delay the development of resistance.⁷ Oral trimethoprim and sulfamethoxazole are readily absorbed from the gastrointestinal tract, widely distributed throughout the body and excreted by the kidneys.⁵

Concomitant host disease influences susceptibility to adverse drug reactions. HIV increases the risk of toxicity with many drugs including co-trimoxazole. Adverse effects occur in up to 65% of those receiving the drug and 50% will discontinue treatment. Hypersensitivity reactions are most common in such patients and include fever and maculopapular rash. Co-trimoxazole is usually well tolerated in immunocompetent patients⁵ but should be avoided in those with severe hepatic or renal dysfunction and porphyria. It is also best avoided during pregnancy and breast-feeding. Side-effects are numerous and include nausea, vomiting, skin reactions, neutropaenia, thrombocytopaenia, hepatitis and cholestatic jaundice.⁸

High dose co-trimoxazole is highly effective and the drug of choice for treatment of PCP. Unfortunately its use is often limited by toxicity so second line treatment options are also needed.⁷

Atovaquone

Atovaquone is a naphthoquinone with broad-spectrum antimicrobial activity.⁹ It is licensed for the treatment of mild to moderate PCP in those who are unable to tolerate co-trimoxazole.⁸ Atovaquone inhibits the binding of microbial ubiquinone to cytochrome b and prevents the synthesis of pyrimidines (organic compounds essential to the production of DNA and RNA). Atovaquone has similar efficacy as pentamidine and is better tolerated than parenteral pentamidine, co-trimoxazole or dapsone. However, oral atovaquone has limited and unpredictable bioavailability.⁹

Clindamycin

Clindamycin binds to the microbial 50S ribosomal subunit and prevents protein synthesis. It is distributed throughout the body and metabolised in the liver before excretion in bile and urine.⁷ Clindamycin is associated with the development of antibiotic-associated colitis and treatment must be immediately discontinued if diarrhoea develops. Other adverse effects include hepatitis, bone marrow suppression and skin reactions.⁸

Dapsone

Dapsone is structurally similar to the sulphonamides and also inhibits the activity of dihydropteroate synthetase, blocking folate synthesis. It has synergistic effects when used with trimethoprim. Dapsone is well absorbed from the gastrointestinal tract and widely distributed throughout the body.¹⁰ Side-effects are common and may include haemolysis, agranulocytosis and hepatic dysfunction.⁸

Pentamidine isetionate

Pentamidine inhibits microbial oxidative phosphorylation and incorporation of nucleic acids into RNA and DNA, leading to inhibition of protein and phospholipid synthesis.⁴ Pentamidine is given intravenously or occasionally in nebulised form in the treatment of PCP. The use of pentamidine is restricted to specialist care, under careful patient observation and with laboratory monitoring. Adverse effects include nephrotoxicity, hypotension, hypoglycaemia, pancreatitis, hepatitis and bone marrow suppression.⁸

Primaquine

Primaquine selectively inhibits the formation of functional transport vesicles and disrupts intracellular secretory mechanisms.¹¹
Primaquine should be avoided in patients with G6PD deficiency as it can cause severe haemolysis. Gastrointestinal side-effects are common.⁸

Specialist treatment must be instituted as early as possible in the clinical course. Severe pneumocystis pneumonia rapidly leads to diffuse alveolar damage, impaired gas exchange and respiratory failure.¹ Arterial blood gas measurement is essential to assess disease severity and guide clinical management. A PaO2 on room air of less than 9.5 kPa signifies severe disease.¹² Mechanical ventilation may be necessary and carries a poor prognosis. Early use of non-invasive methods of ventilation such as continuous positive airways pressure (CPAP) may be beneficial, particularly in the prevention of pneumothoraces.¹³

Mild to moderate pneumocystis pneumonia

Co-trimoxazole is highly effective and is the first choice therapy for mild to moderate PCP. The oral antimicrobial course usually lasts for 21 days but shorter courses may be effective in non-HIV-associated PCP. If co-trimoxazole is not tolerated, alternative treatment regimens may be used.⁷

Atovaquone is licensed as a second line treatment of PCP. The oral course lasts for 21 days but an adequate food intake is required for gastrointestinal absorption. Resistance has been reported with atovaquone monotherapy so it may be advisable to use in combination with pentamidine.⁷

Trimethoprim and dapsone may be used in combination for mild to moderate PCP, although unlicensed.⁸ An alternative regimen should be used in patients with G6PD deficiency.⁷

Clindamycin and primaquine may be the most effective second line regimen in the management of HIV-associated PCP.³ However the combination is associated with considerable toxicity.⁸

Nebulised pentamidine is occasionally used in the treatment of mild disease.⁸ However, trials suggest that it is considerably less effective than parenteral pentamidine, and it should therefore be reserved for patients intolerant of this route.¹⁴

Severe pneumocystis pneumonia

Co-trimoxazole, by intravenous infusion is the optimal treatment for severe disease.⁵

Pentamidine isetionate is used in a slow intravenous infusion as a second line treatment for severe PCP.
80% of patients will respond to treatment but significant adverse effects may occur.⁷

Adjunctive corticosteroid therapy is recommended for HIV-positive patients with severe PCP, to prevent acute respiratory dysfunction and decrease mortality. Although there were initial concerns regarding the use of immunosuppressive drugs in patients who are already gravely immunocompromised, there is no evidence that a short course of corticosteroids increases the risk of serious opportunistic disease or mortality in HIV-infected patients with PCP.¹⁵ Data also suggests that the use of adjunctive high-dose steroids in severe non-HIV-associated PCP may accelerate recovery but more research is needed before recommendations are made for clinical practice.¹⁶ High-dose steroid treatment should be initiated at the same time as antimicrobial chemotherapy and gradually reduced over 2 to 3 weeks.⁷

Drug treatment to protect against recurrence of P. jiroveci is essential after an episode of PCP. Prophylaxis is also recommended for all HIV-positive individuals once their CD4 T cell count falls below 200 cells/mm³⁷ and for other severely immunocompromised patients. Drug prophylaxis reduces the incidence of PCP and lengthens the disease free intervals between episodes.⁴

Drug treatment

Co-trimoxazole is highly effective prophylaxis against PCP⁷ but there is a high rate of discontinuation due to adverse effects, particularly among HIV patients.⁷ Reduced daily dosages or intermittent regimens may improve tolerance.⁸ Co-trimoxazole is also effective against other bacteria and parasites including toxoplasmosis. If co-trimoxazole is not tolerated, second-line agents may be used.¹⁷

Pentamidine may be used as a second-line therapy. Intermittent inhalation of nebulised pentamidine is effective prophylaxis against PCP but due to its limited systemic absorption, extra-pulmonary infections may occur.⁸ Reactivation of toxoplasmosis is common.⁶

Dapsone is the most cost-effective prophylaxis available for PCP but long-term therapy carries risks of serious side-effects.¹⁰ Dapsone is preferred to pentamidine in patients with low CD4 T-cell counts and positive toxoplasma serology.³

Atovaquone is better tolerated than dapsone, so although it is slightly less effective it has a similar overall success rate.⁹

Before the introduction of HAART, the 2-year probability of developing PCP in HIV-positive patients was 40%. HAART has reduced the rate of opportunistic infections and so the absolute benefit of prophylactic treatment in those taking HAART is less significant. Recent studies have suggested that in HIV patients taking HAART with CD4 T-cell counts above 200 cells/ mm³, discontinuation of prophylaxis does not increase the incidence of PCP. Current guidelines recommend that persons who meet these criteria can discontinue PCP prophylaxis and remain off prophylaxis as long as the CD4 T- cell count remains above 200 cells/mm³.¹⁸

Prior to the HIV epidemic, co-trimoxazole was rarely used in developed countries due to concerns regarding toxicity. Resistance to co-trimoxazole in such countries was therefore very low. However since the use of co-trimoxazole and dapsone⁶ for the treatment and long-term prophylaxis of PCP and toxoplasmosis, increased levels of resistance have been detected.¹⁷

A number of single base polymorphisms have been demonstrated in the P. jiroveci nucleotide sequence that codes for dihydropteroate synthetase. These mutations may affect substrate binding and be associated with the emergence of resistance to sulphonamides and dapsone.¹⁹ Mutations in the cytochrome b gene have been demonstrated in atovaquone-resistant P. jiroveci isolates, which are likely to represent mechanisms of resistance.⁹

Findings linking mortality rates to the acquisition of the mutated P. jiroveci organism are inconsistent, which is not surprising, since survival in HIV positive patients depends on many other factors. However, it does make assessment of the impact of drug resistance in such patients difficult, and more research is required to develop strategies to prevent the emergence of further resistance strains.^6,18

New drugs against P. jiroveci are in development. Sordarin derivatives are a novel class of antifungal compounds that inhibit protein synthesis. Animal models of infection have shown promising activity against PCP with limited toxicity. Echinocandins and pneumocandins, which inhibit beta-glucan synthesis are also being investigated.^20,21

The incidence of opportunistic infections is high in patients with immune impairment. PCP remains a common AIDS-defining illness in developed nations and is associated with significant morbidity and mortality. Co-trimoxazole is an effective treatment for PCP but is poorly tolerated. Resistance to anti-pneumocystis drugs is also increasing. The use of HAART and a better understanding of the various parameters of immune deficiencies in HIV may permit more selective use of PCP prophylaxis. This would not only reduce the number of drug-related adverse effects but may decrease selection pressures on resistance genes. Despite this, the issue of resistance remains relevant, and the limited availability of HAART in some areas of the world makes the development of new drugs a continuing priority.³