Ciclosporin is an essential drug in preventing graft rejection after solid organ and hematopoietic stem-cell transplantation. However, it interacts in multiple ways with other drugs and its therapeutic window is narrow. Major and frequent side effects are hypertension and renal failure [1–3].

We report on a 61-year-old woman 5 years after renal transplantation who experienced a nephrotoxic increase in ciclosporin concentrations during antibiotic therapy with tigecycline. The patient was admitted with urinary tract infection caused by E. coli carrying ESBL (extended spectrum β-lactamases) susceptible only to meropenem, gentamicin, and tobramicin. Despite initial improvement under treatment with meropenem, dysuria returned after 5 days, C-reactive protein (CRP) rose and urine culture again yielded E. coli (ESBL) and Staphylococcus epidermidis. To avoid nephrotoxicity of drugs such as gentamicin, antimicrobial therapy was switched to tigecycline.

During intravenous therapy with tigecycline, serum concentrations of ciclosporin rose, closely followed by creatinine levels (max. 167.9 μmol/l) (Fig. 1). The daily dosage of 120 mg ciclosporin had to be reduced by 50% and omitted for 1 day. When tigecycline was discontinued after successful anti-infectious treatment, ciclosporin dosages had to be increased again to the initial dosage of 120 mg daily to maintain therapeutic concentrations. The patient was at no time point septic and despite dysuria in a good condition. During the entire period no other potentially interacting drugs were administered or tapered; in particular no other antibiotics were given. This suggests an interaction between tigecycline and ciclosporin, resulting in increased serum concentrations of ciclosporin.

Fig. 1
figure 1

Concentrations of ciclosporin and serum creatinine are shown in relation to ciclosporin dosage during administration of tigecycline. After start of tigecycline, concentrations of ciclosporin and subsequently of creatinine required a reduction and short interruption of ciclosporin medication. After discontinuation of tigecycline, ciclosporin dosage could be increased up to the initial amount to maintain therapeutic concentrations

Full size image

Ciclosporin displays an oral bioavailability of 20–50%, has a high plasma binding of up to 90%, is mainly metabolised in the liver, and excreted via bile [4]. It is a substrate of the 3A4 and 3A5 members of cytochrome P450 (CYP450) and of the drug efflux pump p-glycoprotein [5]. Concentrations were measured in whole blood prior to the next dose as trough level.

Tigecycline is a new antimicrobial agent of the glycylcycline group with structural similarities to tetracyclines. It inhibits bacterial protein synthesis by binding to the 30S subunit of ribosomes and acts bacteriostatically. One of its major advantages is its ability to overcome the two most important tetracycline resistance mechanisms: ribosomal protection and efflux [6]. In vitro plasma protein binding is approximately 71–89%. It is primarily eliminated via bile (59%); renal excretion (33%) and glucuronidation are secondary ways of elimination. Its elimination half-life is approximately 40 h (37–67 h) [7, 8].

As a relatively new agent, little is known about interactions with other drugs. Potential mechanisms which may explain the pharmacological interaction in our case include the following: (1) In vitro studies showed that tigecycline does not inhibit CYP450, but its influence on CYP450 in vivo cannot be excluded. For instance it has been shown that tigecycline decreases clearance of warfarin, which is also metabolised by CYP450 [9]. (2) Ciclosporin is also a substrate of the multidrug efflux pump p-glycoprotein (p-gp). To our knowledge, possible interactions between tigecycline and p-glycoprotein have not been refuted. Inhibition of p-gp by tigecycline as described for other antibiotics [10] could lead to increased concentrations of ciclosporin. Ciclosporin is measured in terms of whole blood concentrations. Thus, competition of the two drugs for protein-binding sites is not a tenable explanation for the increased levels of ciclosporin.

In our case, 3 days after discontinuing tigecycline, ciclosporin could be given at prior dosage again. The onset of increased ciclosporin concentrations and retention parameters after administrating tigecycline and their normalization after its discontinuation suggest a probable drug-drug interaction [11, 12].

Although tigecycline seemed to be securely administered in combination with ciclosporin, our observations suggest the urgent need for close monitoring of ciclosporin concentrations and retention parameters during treatment with tigecycline.