Interaction between tacrolimus and clindamycin.

Sir,

Tacrolimus is widely used in organ transplantation to prevent allograft rejection. Its hepatic metabolism via cytochrome P450 (CYP) 3A4 represents the major eliminating process. In addition, its bioavailability depends on intestinal P-glycoproteins (PGP) and CYP3A5 activities. Due to its potential toxicity, tacrolimus usage requires a close drug monitoring, as well as the early identification of any pharmacological interaction. Here, we report on a novel interaction between tacrolimus and clindamycin in a renal transplant recipient with Pneumocystis jirovecii pneumonia (PJP).

A 61-year-old woman underwent kidney transplantation from a deceased donor for end-stage renal disease secondary to chronic glomerulonephritis with IgA deposits. Two months later, she presented with grade IV dyspnoea. Maintenance immunosuppression included modified-release (MR) tacrolimus 15 mg/day, mycophenolate mofetil (MMF) 720 mg/day and prednisolone 4 mg/day. Thorax computed tomography showed bilateral ground-glass opacities compatible with PJP, as confirmed by bronchoalveolar lavage analyses. MMF was interrupted, and sulphamethoxazole–trimethoprim (4 × 1280 mg/day) was initiated with methylprednisolone (32 mg/day). The patient's condition declined, requiring mechanical ventilation. From that time, medications were given through a nasogastric tube, and tacrolimus trough level remained stable ∼10 ng/mL while receiving 7 mg/day (Figure 1). Because sulphamethoxazole–trimethoprim treatment induced type IV renal tubular acidosis, antimicrobial therapy was substituted for atovaquone (1500 mg/day) and clindamycin (2400 mg/day IV) on Day 8. Tacrolimus trough level progressively decreased, while its dosage was accordingly increased (Figure 1). Six days later, both atovaquone and clindamycin were interrupted with a progressive return of tacrolimus trough level to baseline. Since the administration of MR tacrolimus through a nasogastric tube may decrease its disposition, the twice-a-day form was initiated (Figure 1). Fibroscopy was performed 10 days after antibiotic withdrawal and disclosed PJP recurrence. Both atovaquone and clindamycin were resumed for 6 days. Again, tacrolimus trough level significantly decreased (Figure 1) though no other medication was initiated. Renal graft function remained stable.

Fig. 1

Changes in tacrolimus blood trough level (nanogram per millilitre) and tacrolimus dose (milligram per day) according to atovaquone/clindamycin therapy from Day 4 at the intensive care unit. Advagraf® and Prograft® represent the modified-release and the twice-a-day form of tacrolimus, respectively.

Because of its extensive metabolism, tacrolimus disposition tightly depends on CYP3A4/5 and PGP activities. Here, a significant decrease of tacrolimus trough level was repeatedly observed when co-administered with atovaquone and clindamycin. Atovaquone is 94% excreted unchanged in faeces, with a modest inhibition of CYP2C19 which is not implicated in tacrolimus metabolism [1]. Conversely, clindamycin metabolism primarily requires its oxidation by CYP3A4/5 and exhibits a clear propensity to induce CYP3A4 activity [2,3]. Thus, similarly to former cases reported under cyclosporine [4], clindamycin may accelerate tacrolimus catabolism. Here, the co-administration of clindamycin and tacrolimus led twice to a significant decrease in tacrolimus trough level. Such temporal relationship is highly suggestive of pharmacological interactions, as supported by a significant Drug Interaction Probability Scale (DIPS) score [5]. In conclusion, the present observation emphasizes the need for a close monitoring of tacrolimus trough level when co-administered with high-dose clindamycin.

Conflict of interest statement. None declared.