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Pneumocystis Jiroveci Pneumonia Prophylaxis After Lung Transplantation: The Bactrim Story...


links image Christopher R. Ensor, PharmD, BCPS-CV
Immediate Past Chair, ISHLT Scientific Council on Pharmacy and Pharmacology
Assistant Professor, Pharmacy and Therapeutics
Clinical Faculty, Thoracic Transplantation
University of Pittsburgh Medical Center, Pittsburgh, PA USA
chris.ensor@gmail.com



Pneumocystis jiroveci is an opportunistic fungus that is recognized as a major public health hazard, particularly for recipients of solid-organ transplantation (SOT) [1]. Pneumocystis jiroveci exists in three known forms: trophozoite, cyst, and sporozoite. Its primary mode of transmission is aerosolization from host-to-host; after which it remains indolent until a period of opportunity for reactivation, such as that experienced during enhanced immunosuppression immediately after transplantation. Risk factors for PJP in lung transplant recipients include immunosuppression intensification, periods of neutropenia, and airway complications. Cytomegalovirus disease enhances the virulence of PJP, increasing the adhesion and replication at least 5-fold over 5 days. Unlike other solid organs, the risk of PJP in lung transplant recipients does not decline over time. The morbidity and mortality experienced after Pneumocystis jiroveci pneumonia (PJP) after lung transplantation is significant; thus, prevention is critical.

The Challenge...

There exists considerable variability in pneumocystis jiroveci pneumonia (PJP) prophylaxis practices amongst lung transplantation programs worldwide [2]. Opinions and practices amongst providers regarding the optimal prophylaxis strategy are generally poorly informed by case experiences and toxicities of one dose or regimen vs. another. Despite recognition that oral sulfamethoxazole/trimethoprim (SMX/TMP) provides optimal prophylaxis, one consistent regimen has not emerged (table) from the breadth of literature [1-6]. Expert opinions generally favor 1 single-strength SMX/TMP tablet daily as a balance between efficacy and toxicity; though, they acknowledge that less-frequent regimens are equally effective [1].

The Data...

First, the study published by Gordon and colleagues from The Cleveland Clinic group describes their experience in 1299 recipients of SOTs between 1987 and 1996 [4]. PJP prophylaxis consisted of 1 double-strength SMX/TMP tablet daily for 1 year in lung transplantation recipients. Of all patients, 25 cases of PJP were identified (4.8 cases per 1000 person-transplant-years [PTY]). Ten of these cases occurred after the first transplanted year, and no cases developed while on PJP prophylaxis. The overall risk of PJP was the highest in lung transplantation (22 cases per 1000 PTY). Risk of PJP within the first year after lung transplantation was 26 cases per 1000 PTY, and subsequently 19.6 cases per 1000 PTY, which indicates that the risk of PJP after lung transplantation does not decline over time. This is a critical point as it supports the practice of life-long PJP prophylaxis after lung transplantation as employed by many centers.

Second, the study published by Wang and colleagues from the Vancouver British Columbia group describes their experience in 1241 recipients of SOTs between 2001 and 2011 [2]. PJP prophylaxis was not defined but was continued for 1 year in lung transplantation recipients. Of all patients, 14 cases of PJP were identified; 7 of which were lung or heart-lung transplant recipients. No cases developed while on PJP prophylaxis. The range of time to diagnosis in lung or heart-lung transplant recipients was 645-1583 days. Here, again, is further substantiating evidence for the unabating PJP risk over time in lung transplant recipients.

Third, and the study that speaks most relevantly to the optimal SMX/TMP regimen, is the meta-analysis (MA) published by Ioannidis and colleagues [6]. This MA included 35 trials and 6583 patients, mostly with human immunodeficiency virus. Irrespective of dosing regimen, SMX/TMP was near universally effective for PJP prevention in patients who did not experience treatment-limiting toxicities. SMX/TMP prophylaxis was clearly more effective than any other regimen (TMP/SMX vs. aerosolized pentamidine [AP]: OR 0.58, 95% CI 0.45-0.75; TMP/SMX vs. dapsone: OR 0.61, 95% CI 0.34-1.1). Toxicities of SMX/TMP were dose-related, and the risk of discontinuation due to adverse effects declined 43% when 1 double-strength tablet was given thrice weekly vs. daily. Moreover, there was a counterintuitive trend towards more PJP cases with higher doses of SMX/TMP (5.9 vs. 1.8 per 100 patient-years) which could be due to suboptimal adherence or discontinuation due to toxicities. Indeed, the discontinuation rate of any oral PJP prophylaxis regimen was higher when compared to AP (OR 5.38, 95% CI 3.69-7.83).

The Conclusion...

Much of these data suffer from three glaring and inalienable limitations: retrospective designs, study location (endemic vs. non endemic areas), and lack of sufficiently large case groups [1-6]. It becomes increasingly difficult to draw meaningful conclusions from these data given these; however, three overarching maxims relevant to PJP prophylaxis lung transplant recipients do emerge: First: life-long prophylaxis should be considered the standard-of-care, Second: SMX/TMP is better than all other agents, and Finally: lower doses of SMX/TMP are reasonably effective with less risk of toxicity when compared to higher doses. At present, each individual center should continually evaluate their local risk-patterns in the context of these data. Consequently, the PJP prophylaxis regimen will, in all likelihood, remain variable across the field.

Table: PJP prophylactic agents [1-8]

 

Agent

Dosing

Toxicity

Mechanistic Targets

First line

Sulfamethoxazole/ trimethoprim (Bactrim, Septra)

1 SS tab PO daily

++

Dihydrofolate reductase and dihydropteroate synthase

1 DS tab PO daily

+++

1 SS/DS tab PO thrice weekly

++

1 SS/DS tab twice weekly

+

Second line

Dapsone (Aczone)

100 mg PO daily

++

Dihydropteroate synthase

Atovaquone (Mepron)

1500 mg PO daily

+

Dihydroorotate dehydrogenase

Third line

Aerosolized pentamidine (Pentam)

300 mg monthly

+

Thymidyate synthase and nucleic acid binding


Disclosure Statement: The author has no conflicts of interest to disclose.


References:

  1. Fishman JA. Prevention of infection caused by pneumocystis carinii in transplant recipients. Clin Infect Dis 2001;32:1397-405.
  2. Wang EHZ, Partovi N, Levy RD, et al. Pneumocystis pneumonia in solid organ transplant recipients: not yet an infection of the past. Transpl Infect Dis 2012;14:519-25.
  3. Munoz P, Munoz RM, Palomo J, et al. Pneumocystis carinii infection in heart transplant recipients: efficacy of a weekend prophylaxis schedule. Medicine 1997;76:415-22.
  4. Gordon SM, LaRosa SP, Kalmadi S, et al. Should prophylaxis for pneumocystis carinii pneumonia in solid organ transplant recipients ever be discontinued? Clin Infect Dis 1999;28:240-6.
  5. Haddad F, Deuse T, Pham M, et al. Changing trends in infectious disease in heart transplantation. J Heart Lung Transplant 2010;29:306-15.
  6. Ioannidis JP, Cappelleri JC, Skolnik PR, et al. A meta-analysis of the relative efficacy and toxicity of Pneumocystis carinii prophylactic regimens. Arch Intern Med 1996;156:177-88.
  7. Nathan SD, Ross DJ, Zakowski P, Kass RM, Koerner SK. Utility of inhaled pentamidine prophylaxis in lung transplant recipients. Chest 1994;105:417-20.
  8. Naik PM, Lyon GM III, Ramirez A, et al. Dapsone-induced hemolytic anemia in lung allograft recipients. J Heart Lung Transplant 2008;27:1198-202.



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