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Table of Contents
CASE REPORT
Year : 2019  |  Volume : 13  |  Issue : 2  |  Page : 147-150

Combination of clindamycin and primaquine for Pneumocystis pneumonia in renal transplant recipients


Department of Nephrology, Aster Medcity, Kochi, Kerala, India

Date of Submission29-Oct-2018
Date of Acceptance01-Feb-2019
Date of Web Publication28-Jun-2019

Correspondence Address:
Dr. V N Unni
Aster Medcity, Kuttisahib Road, Near Kothad Bridge, South Chittoor PO, Cheranalloor, Kochi - 682 027, Kerala
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijot.ijot_72_18

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  Abstract 


Pneumocystis pneumonia (PCP) in kidney transplant recipients is usually treated with trimethoprim-sulfamethoxazole (TMP-SMX). Combination of clindamycin and primaquine (C + P) is recommended for treatment failure. Data are scarce for treatment with C + P in renal transplant recipients. Here, we present three kidney transplant recipients on triple immunosuppression (tacrolimus, mycophenolate mofetil, and prednisolone) diagnosed to have PCP at different time periods after transplant surgery. Bronchoscopy and lavage were done; special staining with Gomori methenamine silver stain demonstrated Pneumocystis jirovecii. Two patients had graft dysfunction at the time of diagnosis. The first patient was started on TMP-SMX but developed leukopenia and was started on oral C + P. The other two cases had graft dysfunction and were started on C + P. All responded to therapy without complications, and improvement in graft function was observed. Clindamycin with primaquine can be considered as a safe and effective option to treat PCP in renal transplant recipients; this combination can replace TMP-SMX, as the first-line therapy, especially in patients with graft dysfunction or leukopenia

Keywords: Clindamycin, Pneumocystis pneumonia, posttransplant infection, primaquine, trimethoprim-sulfamethoxazole


How to cite this article:
Khan MS, Unni V N, Kumar K V, Bipi P K, Jojo P. Combination of clindamycin and primaquine for Pneumocystis pneumonia in renal transplant recipients. Indian J Transplant 2019;13:147-50

How to cite this URL:
Khan MS, Unni V N, Kumar K V, Bipi P K, Jojo P. Combination of clindamycin and primaquine for Pneumocystis pneumonia in renal transplant recipients. Indian J Transplant [serial online] 2019 [cited 2019 Sep 15];13:147-50. Available from: http://www.ijtonline.in/text.asp?2019/13/2/147/261848




  Introduction Top


Pneumocystis jirovecii is an opportunistic fungal pathogen that causes life-threatening infection in immunocompromised individuals. The incidence of Pneumocystis pneumonia (PCP) among solid-organ transplant recipients ranges from 5% to 15%, depending on the organ transplanted and the immunosuppressive drug regimen used. In kidney transplant recipients, the reported incidence is 0.4–2.7/1000 patient-years.[1] Pneumocystis jirovecii pneumonia commonly occurs in the first 2–6 months after transplantation. The first-line drug for treatment is trimethoprim-sulfamethoxazole (TMP-SMX). Alternative drugs, also called the second-line drugs, include intravenous pentamidine, dapsone, and combination of clindamycin and primaquine (C + P).[2]


  Case Report Top


We report three kidney transplant recipients presenting with fever for evaluation, at different time periods after transplantation. At our center, all transplant recipients receive TMP-SMX for the first 6 months. Clinical characteristics of all three patients are summarized in [Table 1] and laboratory parameters are summarized in [Table 2]. All were on maintenance immunosuppression (tacrolimus [0.1 mg/kg/day], mycophenolate mofetil [1 g twice daily], and prednisolone [0.5 mg/kg/day, tapered to 5 mg/day in 3 months]); tacrolimus levels after 3 months were targeted between 4 and 6 ng/ml. Patient 1 underwent second kidney transplantation and he was given antithymocyte globulin (ATG) along with three sessions of plasma exchange before transplant, as the donor-specific antibody was positive. Patient 2 had acute cellular rejection at 10 months after transplant and had received three doses of intravenous methyl prednisolone (500 mg). Blood sugars were normal in all. X-ray chest [Figure 1]a, [Figure 1]b, [Figure 1]c was abnormal in Patient 1, but near normal in Patients 2 and 3. There was poor correlation with high-resolution computed tomography (HRCT) chest findings, which showed bilateral extensive ground-glass opacities [Figure 2]a, [Figure 2]b, [Figure 2]c. Bronchoscopy and bronchoalveolar lavage (BAL) were done in all patients and subjected to special stain (Gomori methenamine silver [GMS]), which confirmed PCP [Figure 3]. Patient 1 was started on TMP-SMX (Dose: TMP: 15–20 mg/kg/day and SMX: 75–100 mg/kg/day); he developed severe leukopenia; the drug was discontinued and was started on oral C + P. Patients 2 and 3 had renal insufficiency. They were treated with oral clindamycin (600 mg, thrice daily) + primaquine (30 mg, once daily) for 21 days as the first-line therapy. Adjunctive prednisolone was also given for 3 weeks; 40 mg twice daily for 5 days, followed by 40 mg daily for 5 days and then 20 mg daily for 11 days. The dose of mycophenolate mofetil was also reduced.
Table 1: Demographic and clinical characteristics

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Table 2: Investigations (at admission)

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Figure 1: X-ray chest at diagnosis (a: Patient 1) Diffuse reticulonodular shadowing (b: Patient 2) Prominent bronchovascular markings in bilateral hilar regions (c: Patient 3) Prominent bronchovascular markings

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Figure 2: High-resolution computed tomography chest at diagnosis (a: Patient 1) Bilateral alveolar ground-glass and dense opacity in the upper and middle lobes (b: Patient 2) Multiple ground-glass nodules in all lobes, more in the right upper and lower lobes (c: Patient 3) Bilateral diffuse ground glassing with reticular septal thickening

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Figure 3: Bronchoalveolar lavage fluid: Gomori methenamine silver stain: stained cyst walls (thick arrow); alveolar cast (thin arrow); organisms appear as folded spears

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All three patients tolerated the medications and had complete resolution of symptoms in 3 weeks. Clinical characteristics after treatment are summarized in [Table 3]. Imaging of chest showed complete resolution of lesions [Figure 4]a, [Figure 4]b, [Figure 4]c. No adverse effects were noted with C + P combination therapy.
Table 3: Clinical and diagnostic parameters after treatment (after 3 weeks of C + P)

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Figure 4: Imaging after 3 weeks of treatment with C + P (a: Patient 1) improved significantly (b: Patient 2) normal (c: Patient 3) normal

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  Discussion Top


PCP is an opportunistic infection that typically presents in the first 6 months after renal transplantation, with fever, nonproductive cough, effort intolerance, low oxygen saturation, and diffuse interstitial infiltrates on radiograph of the chest. All three of our patients had fever and cough; two of them had low oxygen saturation on presentation. Two patients developed PCP in the 1st year after transplant and the third patient developed after 8 years.

Risk factors for PCP include use of ATG, corticosteroids, mycophenolate mofetil, calcineurin inhibitors, cytomegalovirus disease, low CD4+ T cell counts, neutropenia, and most importantly exposure to patients with PCP. ATG induction has been reported to be the highest risk factor for PCP,[2] as seen in our first patient who developed infection in spite of receiving PCP prophylaxis. In our institute, we give PCP prophylaxis with TMP-SMX for all kidney transplant recipients for the first 6 months after renal transplantation. Other risk factors include use of antirejection therapy,[3] as seen in our second patient, who had received three doses of intravenous methyl prednisolone.

HRCT scans are more sensitive than radiograph of the chest and may show ground-glass opacities with sparing of lung periphery;[4] this was noted in our cases, where two patients had near-normal X-ray chest and HRCT chest was clearly abnormal. BAL microscopy and staining is a highly sensitive method of diagnosing PCP and has a yield of 80%.[2] All the three cases underwent BAL with special staining with GMS stain, which can identify cell wall of the cysts.[2] In all three cases, GMS stain was positive and diagnosis was established by demonstrating the organism; polymerase chain reaction (PCR) was positive for Pneumocystis jirovecii. PCR with sputum and BAL fluid samples have a high sensitivity and specificity for the detection of the organism, but lacks utility in diagnosing PCP, as PCR cannot differentiate colonization from infection. However, PCR has a negative predictive value of 100%.[1]

TMP-SMX is the first-line agent and is quoted as the drug of choice.[5] No agent has been shown to have a superior outcome. Patient 1 was started on therapeutic dose of TMP-SMX; there was a fall in total leukocyte count, TMP-SMX was stopped, and he was started on oral C + P. Leukopenia is a known complication of TMP-SMX, risk is higher when used in combination with an antimetabolite; TMP-SMX causes a dose-dependent leukopenia,[6] and a high dose of TMP-SMX (TMP: 15–20 mg/kg/day and SMX: 75–100 mg/kg/day) is recommended for treating PCP; however, there is no reported risk of leukopenia with C + P. TMP-SMX is associated with thrombocytopenia as well; generation of antibodies to glycoprotein IIb/IIIa complex on platelets can cause immune thrombocytopenia which is most commonly seen in within 1st week of treatment and is reversible on stopping the drug,[6] there is no risk for thrombocytopenia with C + P. Hyperkalemia is also seen in 6% of patients receiving TMP-SMX;[6] however, incidence can go up to 50% in those with graft dysfunction.[7] In Patient 2, there was moderate renal failure (serum creatinine: 4.56 mg%), renal dose modification is needed for TMP-SMX and requires drug level monitoring.[6] Therefore, TMP-SMX was not considered and he was started on oral C + P. There is no need for dose modification and drug level monitoring for C + P. Patient 3 also had graft dysfunction and was started on oral C + P. There is a consensus for adjunctive steroid therapy in HIV-infected patients,[8] the dose recommended was used in our patients for 3 weeks, which they tolerated well.

All three patients showed clinical improvement and recovered completely.Oral therapy with C + P is adequate because the oral bioavailability of clindamycin is 90% and primaquine is 96%. Moreover, primaquine is not available in parenteral form; however, we agree parenteral clindamycin can be considered to have an edge over the oral regimen. Graft functions showed an improvement. No adverse effects of the drugs were noted. There are no drug interactions of C + P with tacrolimus and mycophenolate mofetil. Most of the data on C + P for treatment of PCP comes from HIV-infected patients. The first study done exclusively in renal transplant recipients to assess TMP-SMX versus C + P for treatment of PCP was reported in 2014.[9] The failure rate of TMP-SMX was more than C + P group, and half of the treatment failure in TMP-SMX group were attributed to adverse drug effects; no adverse drug effects were seen in the C + P group.[9] An Indian study also reported, adverse effects of TMP-SMX was seen in 44% of patients; they were eventually switched over to C+P;[7] the authors reported that superiority of TMP-SMX in the treatment of PCP compared to C + P is marginal.[7],[9]


  Conclusion Top


PCP in kidney transplant recipients can be safely and effectively treated with C + P, without any major drug-related side effects. There is need for further studies to conclude if C + P is noninferior to TMP-SMX in renal transplant recipients with graft dysfunction.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Archuleta S. Pneumocystis pneumonia in transplant recipients. J Fungi 2015;1:293-31.  Back to cited text no. 1
    
2.
Martin SI, Fishman JA; AST Infectious Diseases Community of Practice. Pneumocystis pneumonia in solid organ transplantation. Am J Transplant 2013;13 Suppl 4:272-9.  Back to cited text no. 2
    
3.
Struijk GH, Gijsen AF, Yong SL, Zwinderman AH, Geerlings SE, Lettinga KD, et al. Risk of pneumocystis jiroveci pneumonia in patients long after renal transplantation. Nephrol Dial Transplant 2011;26:3391-8.  Back to cited text no. 3
    
4.
Hidalgo A, Falcó V, Mauleón S, Andreu J, Crespo M, Ribera E, et al. Accuracy of high-resolution CT in distinguishing between pneumocystis carinii pneumonia and non- pneumocystis carinii pneumonia in AIDS patients. Eur Radiol 2003;13:1179-84.  Back to cited text no. 4
    
5.
Goto N, Oka S. Pneumocystis jirovecii pneumonia in kidney transplantation. Transpl Infect Dis 2011;13:551-8.  Back to cited text no. 5
    
6.
Ho JM, Juurlink DN. Considerations when prescribing trimethoprim-sulfamethoxazole. CMAJ 2011;183:1851-8.  Back to cited text no. 6
    
7.
Jairam A, Dassi M, Chandola P, Lall M, Mukherjee D, Hooda AK, et al. Pneumocystis jiroveci outbreak in a renal transplant center: Lessons learnt. Indian J Nephrol 2014;24:276-9.  Back to cited text no. 7
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8.
National Institutes of Health-University of California Expert Panel for Corticosteroids as Adjunctive Therapy for Pneumocystis Pneumonia. Consensus statement on the use of corticosteroids as adjunctive therapy for pneumocystis pneumonia in the acquired immunodeficiency syndrome. N Engl J Med 1990;323:1500-4.  Back to cited text no. 8
    
9.
Nickel P, Schürmann M, Albrecht H, Schindler R, Budde K, Westhoff T, et al. Clindamycin-primaquine for pneumocystis jiroveci pneumonia in renal transplant patients. Infection 2014;42:981-9.  Back to cited text no. 9
    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4]
 
 
    Tables

  [Table 1], [Table 2], [Table 3]



 

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