1. Role of co-trimoxazole infusion in the management of of Pneumocystis (carinii)jirovecii pneumonia in HIV infected patients
Dr. Bruce Kirenga
GSKI/SEP-PPT/01/04/11

2. Introduction PCP Epidemiology
Pneumocystis pneumonia in humans is caused by P. Jirovecii rather than P. Carinii found in rats.
In 1988 it was identified as a fungus based on DNA analysis.
P. Jirovecii has maintained it’s importance because of it’s frequent presentation in pneumonia patients with T cell mediated immunodeficiency.
GSKI/SEP-PPT/01/04/11

3. Prevalence of PCP pre-HAART/COTRIP

4. PCP post HAART & COTRIP

5. Pneumocystis jirovecii Pneumonia: Clinical manifestations
P. jirovecii is acquired by inhalation.
Presentation can vary with patients usually ill for 2 to 3 weeks
Progressive dyspnoea
Dry cough
Tachycardia
Tachypnea
Hypoxia
Low grade fever
GSKI/SEP-PPT/01/04/11

6. Pneumocystis jirovecii Pneumonia: Diagnosis
Lung auscultation in comparison to symptoms is usually unremarkable
Blood gas analysis demonstrates respiratory alkalosis
Oxygen desaturation of ≥ 5% with exercise is a reliable quick test.
Early disease chest X-ray may be normal but will classically show fine bilateral diffuse infiltrates
GSKI/SEP-PPT/01/04/11

7. Pneumocystis jirovecii Pneumonia: Diagnosis
CAT scans are more effective than Chest radiography in the diagnosis of PCP
Definitive diagnosis in based on identification of the organism on histopathology
Sputum induction with hypertonic saline has a diagnostic yield ranging from 50%-90% and specificity approaching 100%
Fibreoptic bronchoscopy has >90% sensitivity and 100% specificity
GSKI/SEP-PPT/01/04/11

8. Pneumocystis jirovecii Pneumonia: Diagnosis
Immunofluorescent staining of bronchial specimens is the most sensitive and specific diagnostic test readily available.
PCR testing of induced sputum can also be used.
However no commercial PCR test is broadly available at this time.
GSKI/SEP-PPT/01/04/11

9. Pneumocystis jirovecii Pneumonia: Treatment
Untreated PCP is almost always fatal.
In patients without HIV infection response to treatment should begin in 4 to 5 days.
In patients infected with HIV, the treatment response takes longer but should occur within the first 8 days.
It is not uncommon to observe clinical deterioration in the first 24 hours of the initiation of therapy especially in moderate to severe cases.
GSKI/SEP-PPT/01/04/11

10. Pneumocystis jirovecii Pneumonia: Treatment
The length of treatment is 21 days in HIV infected patients and 14 days in non-HIV infected individuals.
It is common practice to extend therapy if there is a delay in resolution of signs and symptoms.
A longer duration of treatment in HIV infected individuals is often needed due to the larger burden of organisms and the slower response to therapy.
GSKI/SEP-PPT/01/04/11

11. Pneumocystis jirovecii Pneumonia: Treatment
In general the parenteral route is preferred for administering antibiotics for moderate to severe disease.
Antibiotics are the mainstay of treatment for PCP
The dosages of medications must be adjusted for renal and hepatic impairment.
GSKI/SEP-PPT/01/04/11

12. Pneumocystis jirovecii Pneumonia: Treatment options
Regimen
Dosage
Contraindications
Common adverse effects
Co-Trimoxazole
The recommended dose for treatment of PCP/PJP is 20mg/kg of Trimethoprim a day and 100mg/kg of Sulfamethoxazole per day in two to four divided doses.
Hypersensitivity, megaloblastic anemia due to folate deficiency
Toxicities include:
Skin reactions including mild rash to anaphylaxis.
Drug fever
Bone marrow suppression
Nausea
Vomiting
Diarrhoea
Pancreatitis
Metabolic acidosis
hyperkalemia
Dapsone
100mg daily
Hypersensitivity, G-6-PDdeficiency
Haematological side effects anaemia, methemoglobinemia, haemolysis in patients with G6PDH deficiency
Fever
Peripheral motor weakness
Dose unrelated granulocytopenia
Aplastic anaemia
Coetaneous reactions.
Clindamycin
900mg IV every 8 hours
Hypersensitivity, regional Enteritis, ulcerative colitis, Hepatic impairment, antibiotic associated colitis
Diarrhoea, nausea, vomiting, rash , clostridium difficile associated colitis
GSKI/SEP-PPT/01/04/11

13. Pneumocystis jirovecii Pneumonia: Treatment
Regimen
Dosage
Contraindications
Common adverse effects
Atavaquone
750mg PO BID
Hypersensitivity
Adverse reactions include skin rash, fever, GI symptoms and abnormal liver function.
Pentamidine
4mg/kg/ per day IV or IM
Hypersensitivity,
Hypotension
Nausea
Vomiting
Pruritus
Unpleasant taste
Hallucinations
Syncope
Pain at injection site and
development of a sterile abscess
in IM administration
Urticaria
Venous thrombosis in IV
administration
Timetrexate
45mg/m2 IV QID
Hypersensitivity, severe myelosupression
Side effects include: myelosuppression ( neutropenia and thrombocytopenia)
Increase serum transaminase, creatinine, anemia, fever , rash and pruritus.
Primaquine
15-30mg PO
Hypersensitivity, G-6-PDdeficiency
Haemolytic anemia, methemoglobinemia, leucopoenia, nausea, vomiting, epigastric pain
GSKI/SEP-PPT/01/04/11

14. Pneumocystis jirovecii Pneumonia: Trimethoprim Sulfamethoxazole
Co-trimoxazole is the drug of choice for pneumocystis.
It is made up of two anti-microbial agents that act synergistically against a wide range of bacteria
When Trimethoprim and Sulfamethoxazole maximum inhibition of most susceptible bacterial occurs when the ratio is respectively 1:20
The drug is available as a higher fixed ration of 1:5
GSKI/SEP-PPT/01/04/11

15. Pneumocystis jirovecii Pneumonia: Trimethoprim Sulfamethoxazole
This regimen has been widely recommended as the first line therapy for HIV related PJP/ PCP32
This combination has the advantage of comparatively favourable toxicity profile, long track record and easy availability33-36
demonstrate 86% patients treated with Co-trimoxazole survived without respiratory support at completion of treatment compared to 61% on Pentamidine37
GSKI/SEP-PPT/01/04/11

16. Pneumocystis jirovecii Pneumonia: Trimethoprim Sulfamethoxazole
The mechanism of action of co-trimoxazole involves sequential inhibition of folate biosynthesis by the organism.
Sulfamethoxazole inhibits dihydropteroate synthase which catalyses the condensation of p-aminobenzoic acid and 6-hydroxymethyl -7,8- dyhydropterin pyrophosphate to form dihydropteroate.
GSKI/SEP-PPT/01/04/11

17. Pneumocystis jirovecii Pneumonia: Trimethoprim Sulfamethoxazole
Trimethoprim inhibits microbial dihydrofolate reductase and therefore inhibits purine synthesis.
It therefore prevents deoxyribonucleic acid ( DNA ) production.
This sequential inhibition of folic acid synthesis results in synergistic microbial kill.
GSKI/SEP-PPT/01/04/11

18. Pneumocystis jirovecii Pneumonia: Trimethoprim Sulfamethoxazole
absorption is unaffected by food.
Bioavailability is approximately 85% for both compounds.
Peak concentrations are achieved within 2-4 hours with oral therapy and 1-2 hours with parenteral therapy.
GSKI/SEP-PPT/01/04/11

19. Pneumocystis jirovecii Pneumonia: Trimethoprim Sulfamethoxazole
CSF penetration is good with Trimethoprim concentrations ranging from 20% to 60% and Sulfamethoxazole 12% to 50%.
The recommended dose for treatment of PCP/PJP is 20mg/kg of Trimethoprim a day and 100mg/kg of Sulfamethoxazole per day in two to four divided doses.
GSKI/SEP-PPT/01/04/11

20. Pneumocystis jirovecii Pneumonia: Trimethoprim Sulfamethoxazole Toxicities
Toxicities include:
Skin reactions including mild rash to anaphylaxis.
Drug fever
Bone marrow suppression
Nausea
Vomiting
Diarrhoea
Pancreatitis
Metabolic acidosis
hyperkalemia
GSKI/SEP-PPT/01/04/11

21. Pneumocystis jirovecii Pneumonia: Trimethoprim Sulfamethoxazole Toxicities
Nephrotoxicity with Co-trimoxazole is uncommon
Co-trimoxazole desensitization could potentially allow for its use in those with hypersensitivity reactions.
Desensitization should never be attempted in patients whose adverse events involves severe rash with mucosal involvement.
adverse reactions are managed with supportive care and discontinuation of drug.
GSKI/SEP-PPT/01/04/11

22. Pneumocystis jirovecii Pneumonia: Adjunctive therapy
Steroids are recommended for moderate to severe PCP arterial oxygen pressure ≤ 70mmHg
Steroid given no later than 72 hours after initiation of therapy
The regimen consists of prednisone 40mg orally twice daily for the first 5 days and 20mg orally once daily for an additional 11 days.
GSKI/SEP-PPT/01/04/11

23. Pneumocystis jirovecii Pneumonia: Adjunctive therapy
Adjunctive steroids improve survival, decrease respiratory decompensation, and need for mechanical ventilation.
Steroids blunt the inflammatory response of dying organisms that result in lung tissue damage.
GSKI/SEP-PPT/01/04/11

24. Pneumocystis jirovecii Pneumonia: Anti-retroviral therapy
Optimal timing of ART is a subject of debate.
Immune reconstitution and inlammatory response (IRIS) with paradoxical worsening of PCP and other OI on initiation of ART.
The first study looking at use of ART in severe PCP indicated mortality of 63% in those not receiving ART vs 25% in those on ART.
GSKI/SEP-PPT/01/04/11

25. Pneumocystis jirovecii Pneumonia: Considerations in Pregnancy
Preferred treatment: Sulfamethoxazole and Trimethoprim
Pentamidine embryo toxic in animals
trimetrexate teratogenic in animals
Corticosteroid indications as in non pregnant
women monitor for hyperglycemia
GSKI/SEP-PPT/01/04/11

26. Pneumocystis jirovecii Pneumonia: Considerations in Pregnancy
If sulfamethoxazole or dapsone used near delivery, theoretical increased risk for hyperbilirubinemia and kernicterus
Increased risk of preterm labor and delivery; monitor if pneumonia occurs after 20 weeks of gestation
GSKI/SEP-PPT/01/04/11

27. References:
Jose G. Castro, Morrison-Bryant Maya, HIV / AIDS- Research and Palliative care 2010:
32 Centres for disease control and prevention. Guidelines for Prevention and Treatment of Opportunistic Infections in HIV infected adults and adolescents, Recommendations from the CDC, the National institutes of health and the HIV medicines association of the Infectious Diseases Society of America MMWR 2009;58:6-10
33 Hughes WT. Trimethoprim-Sulfamethoxazole therapy for Pneumocystis carinii pneumonitis in children. Rev Infect Dis. 1982;4:
34 Lowell S. Young. Trimethoprim-Sulfamethoxazole in the treatment of adults with pneumonia due to Pneumocystis carinii. Rev Infect Dis. 1982;4:
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28. References:
35 Hughes W, Feldman S, Chaudhary S, et al. Comparison of Pentamidine isethionate and Trimethoprim – Sulfamethoxazole in the treatment of Pneumocystis carinii pneumonia. J Paediatr. 1978;92:
36 Winston DJ, Lau WK, Gale RP, Young LS. Trimethoprim – Sulfamethoxazole for the treatment of Pneumocystis carinii pneumonia. Ann Intern Med. 1980;92:
37 Sattler FR, Cowan R, Nielsen DM, Ruskin J. Trimethoprim- sulfamethoxazole compared with Pentamidine for treatment of Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome. Ann Intern Med 1988; 109:
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29. Pneumocystis jirovecii Pneumonia: Conclusions
Despite knowledge and advances in prevention and management of PCP it continues to have high morbidity and mortality rates.
Trimethoprim with Sulfamethoxazole remains the recommended first line treatment.
It is currently the most effective medication for its prevention and treatment.
This combination has the advantage of comparatively favourable toxicity profile, long track record and easy availability.
GSKI/SEP-PPT/01/04/11