Chemoprophylaxis of fungal infections in organ transplantation: who, when, how?

B. RammaertO. Lortholary

Abstract: 

Chemoprophylaxis of invasive fungal infections (IFIs) transplanted solid organ patients remains complex and controversial because few studies available on the subject. Although the risk of IFI persists throughout the immunosuppressive therapy, organ transplantation majorises it in in post-transplant 100 days [1,2]. An observational study involving 23 centers in the US transplantation showed that invasive candidiasis accounted for 53% of the IFI mostly with species non- albicans from Candida, followed by invasive aspergillosis (19%), the cryptoccocose (8%), the infections in other molds that Aspergillus spp. (8%), endemic mycosis (5%) and mucormycosis (2%) [3]. Three parameters must be taken into account in assessing the fungal risk in organ transplant population: the type of transplant, the concept of colonization and geographical location.

First, the fungal risk is ubiquitous when it comes to Candida spp., Aspergillus spp., Pneumocystis jirovecii orCryptococcus spp. The type of transplanted organ is however to be taken into account in assessing this risk, the foreground hail transplant followed by heart-lung transplants and liver [4].

Candida spp. is responsible for early infections within 30 days post-transplant mainly in liver transplant patients, pancreatic and intestinal [4,5]. A fluconazole prophylaxis is recommended. However, it does not reduce overall mortality even if it reduces the number of acute episodes of candidiasis and is purveyor of infections with Candidanon albicans in the liver transplant population [5]. We must differentiate between patients at low and high risk for IFIs. Prophylaxis remains controversial in the low risk category, so it is recommended for patients with at least two risk factors for candidiasis [6-9].

Among lung transplant, the pretransplant colonization with Aspergillus spp. significantly increases the risk of invasive aspergillosis tracheobronchitis in post-transplant [10]. Similarly, bronchial colonization in post transplantation increases by 6 to 11 times the risk of invasive aspergillosis [11]. Therefore, in colonized patients before transplantation, an anti-Aspergillus prophylaxis should be begun and continued 2-6 months post-transplant. In colonized patients after transplantation, prophylaxis should be continued during the first 6 months [10]. In liver and heart transplant, a number of risk factors have been described, such as CMV infection or renal failure, leading to propose a prophylactic anti- Aspergillus in very specific situations. [12]

The risk of pneumocystis is major in the first 6 months post-transplantation especially heart-lung transplantation. [13] In addition, outbreaks have occurred in renal transplantation involving human transmission. [14] The risk factors are well known: increased immunosuppression, rejection episodes, concomitant CMV infection, CD4 + cell counts low. Some authors suggest continuing antifungal prophylaxis in renal transplant patients with low CD4 + lymphocytes (<200 / mm3) beyond the first 6 months post-transplant. [15]

The overall incidence of cryptococcosis in the transplanted remains low at about 1.8%. [16] It occurs relatively late post-transplant period, between 16 and 21 months depending on the [16] studies. The occurrence of cryptococcal early after transplantation, particularly in the month following transplant, may be due to transmission by the [16] graft. In addition, subclinical reactivation of cryptococcosis may be involved in the occurrence of this infection, median 5.6 months post-transplantation in the transplant, without this leading to formal recommendations of antifungal prophylaxis [17,18] .

Second, the fungal risk varies depending on the endemic area. There are 3 modes of acquiring these endemic fungal infections: primary infection, reactivation of latent infection, transmission by the graft.

Coccidioidomycosis is endemic in the southwest of the USA, Central America and some countries in Latin America. The risk is greatest in the year following transplantation especially in lung and liver transplant patients with an incidence of 4 to 9% [19-21]. Seropositive and / or a history of coccidioidomycosis before transplant, or the treatment of acute rejection are known factors of post-transplant infection [22]. Coccidioidomycoses of reactivations are possible despite a well conducted antifungal prophylaxis and when the donor is infectedCoccidioides spp. [20,23]. Histoplasmosis and blastomycosis are endemic both in the US [24]. The incidence of blastomycosis in the transplanted organ is lower than that of histoplasmosis or coccidioidomycosis. [25] No prophylaxis is therefore recommended. About histoplasmosis, the overall incidence of 1 case per 1000 person-years with average delays of 17 months (8.1 to 46) post-transplant. [26] The lung transplant and pancreas are more likely than other patients. Cases of infection have been described graft, requiring prophylaxis in [26] recipient.

The chemoprophylaxis generally débutées immediately post-transplant. We must of course take account of drug interactions between immunosuppressants and antifungal and reduce eg a 1/3 doses of tacrolimus when used in combination with voriconazole [11]. On the other hand, the fungal colonization must allow to select a molecule suitable for Antifungal. No study has used the IFI prophylaxis posaconazole in transplanted solid organ while it is commonly used in transplant of marrow or neutropenic patients [27]. The duration of prophylaxis are not clearly defined due to lack of education. The indications and prescribing terms are grouped in Table 1.

In conclusion, the fungal risk is well established for the most common IFI early post-transplant period. However, few formal recommendations for primary prophylaxis were issued. Screening for pre-transplant fungal infections and particularly in areas of endemic mycoses, may allow targeting at-risk populations and thus offer an appropriate antifungal prophylaxis.

Table 1. antifungal chemoprophylaxis among organ transplant

IFI

Indication Transplant

primary prophylaxis

doses

term post-transplant

ref

aspergillosis

pulmonary

Voriconazole IV / PO

6 mg / kg / dose IV doses x2 then 200mg / 12h

4 month minimum, longer if rejection or settlement

[11]

itraconazole PO

200mg / 12h

6 months

[28], [29]

Lamb aerosols

25mgx3 / wk 60j then 25mg / week 120J then 25mg / 15j

Min 6 months

[thirty]

cardiac high-risk g

itraconazole

Lamb aerosols

200mg / 12h

50-100mg / week

50-150j

[12], [31]

high-risk liver ¨

LAMB

caspofungin

3-5mg / kg / day

J1 70mg, 50mg / day maintenance

4 weeks

[12]

candida

high-risk liver *

fluconazole

200-400mg / day

At least 7-14j

[32,33]

LAMB

1-2mg / kg / day

At least 7-14j

[8,34]

pancreatic

fluconazole

Lamb λ

400mg / d

3-5mg / kg / day

≥4semaines

[5]

intestinal

fluconazole

Lamb λ

400mg / d

3-5mg / kg / day

2-4sem

[5], [7]

coccidioidomycosis

 

Risk of reactivation,

latent infection

Graft infection

fluconazole

200-400mg / day

At least 6 months

[35]

histoplasmosis

Risk of reactivation,

latent infection

Graft infection

itraconazole

200mg / d

3-18 months

[26]

pneumocystosis

All kinds ®

cotrimoxazole

dapsone

atovaquone

800mg / d #

100mg / d

X2 750mg / d

Minimum 6 months

[29]

Lamb: liposomal amphotericin B; g defined by Aspergillus in BAL, reoperation, CMV, post-transplant hemodialysis, aspergillosis 2 months before the transplant; * Defined by re-transplantation serum creatinine> 2.0 mg / dL, cholédochojéjunostomie, intraoperative blood transfusion> 40U, prolonged surgery (> 1 h), fungal colonization detected at least 2 days before and 3 days after transplantation; ¨ defined by retransplantation, reoperation, renal dysfunction requiring treatment, transplantation for fulminant hepatitis, CMV, HCV, prolonged resuscitation; λ in centers with high prevalence of Candida non albicans ; ® when prednisone> 20mg / d and other immunosuppressive T or CD4 +> 200 / mm 3 ; # alternative dosage: 400mg / day or 800mg x3 / week

2011

Full conference title: 

Réunion Interdisciplinaire de Chimiothérapie Anti Infectieuse
    • RICAI 31st (2011)