A highly concentrated tigecycline lock solution ensures in vivo activity against staphylococcal catheter-related infections

Sir,

We read with interest the report of Lebeaux et al.1 recently published in this journal. We share a similar interest in finding the drug or combination of drugs that achieves biofilm eradication in intravascular devices. Tigecycline is an antimicrobial with still little evidence regarding its use as lock treatment (i.e. antimicrobial lock) for long-term catheter-related bloodstream infection (CRBSI).2,3In vitro catheter-infection models show that staphylococcal biofilm eradication can be achieved after 72 h of tigecycline exposure.4

No visual incompatibilities with drugs, such as N-acetylcysteine, EDTA or heparin, have been reported. However, it has been described that tigecycline and EDTA combinations change coloration from yellow to dark brown when syringes are stored for more than 48 h at 25°C or 37°C.5

The rationale for an antimicrobial lock is to ensure that biofilms that develop inside the catheter lumen are exposed to the highest concentration of an antimicrobial, in order to achieve bacterial eradication.6 However, because of the difficulty in conducting research, the optimal time for replacing an antimicrobial lock solution remains unanswered. At the same time, therapeutic options for Gram-positive CRBSI are narrowing. Tigecycline lock solutions are still an insufficiently explored option for the treatment of CRBSI. For this reason, we have studied the visual compatibility, antimicrobial activity and anticoagulant efficacy of a 4500 mg/L tigecycline lock solution after 7 days of continuous in vivo catheter lock in our hospital. The study had the approval of the ethics committee. All patients signed the informed consent form.

A total of 20 patients, 12 women and 8 men, with a mean age of 55.97 years (IQR: 67.49–49.71 years) and with an indwelling venous access port were divided into four groups of five patients each. Each of them received a lock solution that combined 50 mg of tigecycline plus 1000 IU of sodium heparin for a range of 1–7 days. Median time of port implantation was 35.78 days (IQR: 3.93–726.85 days). After completion of 1, 3, 5 and 7 days of lock, a 2 mL sample was drawn from each port to determine tigecycline concentration by HPLC. Subsequently, antimicrobial activity of the recovered samples against Staphylococcus aureus subsp. aureus ATCC® 29213™ was determined by a microdilution method according to CLSI recommendations.7 Additionally, antimicrobial activity of the recovered samples from ports was evaluated by a metabolic assay against a 24 h staphylococcal biofilm.8 Biofilms were incubated in the dark with 10 mg/L resazurin at 35°C for 24 h. Resazurin is reduced to resorufin, which is fluorescent. Fluorescence was measured at a wavelength of 590 nm. All bioassays were performed in triplicate.

The mean tigecycline concentration was 1060 mg/L (IQR: 960–1220 mg/L) after 7 lock days. When compared with that of the instilled lock solution, the antimicrobial concentration had decreased by 76.44% (IQR: 980–1240 mg/L; P = 0.043) after 7 lock days. The recovered lock solution MIC for planktonic S. aureus was 0.25 mg/L (min-max: 0.25–0.25 mg/L) after 1 lock day, and it remained unchanged throughout the 7 lock days. Similarly, metabolic activity of non-planktonic S. aureus was reduced by 90% ± 3% when biofilms were exposed to the samples recovered from ports after 7 lock days. Resazurin bioassays showed that tigecycline concentrations between 4 and 2250 mg/L reduced metabolic activity of non-planktonic S. aureus in biofilm by only 20% ± 3% when compared with the 4500 mg/L solution instilled into the ports.

Anticoagulant activity of sodium heparin in lock solutions was not altered after 7 in vivo lock days, as 90% of the recovered samples showed a non-coagulable activated thromboplastin time (aPTT) assay (P > 0.05). None of the patients in our study experienced any thrombotic complication.

Samples recovered from ports gradually darkened as the days progressed. After 5 lock days, all samples showed macroscopic changes, turning dark brown with apparent precipitates that were still present despite double centrifugation at 2500 rpm for 10 min. Darkening of tigecycline solution had been described in an in vitro compatibility study.9 However, to our knowledge, this is the first time that tigecycline plus heparin at a concentration of 4500 mg/L had been used for continuous in vivo antimicrobial lock for 7 days. From our experience, we report that a 4500 mg/L tigecycline lock solution is safe and assures antimicrobial concentrations 4000 times over S. aureus MIC for 7 days.10 At the same time, tigecycline solution indwelled into the ports remains active against planktonic S. aureus throughout the lock time period and reduces the metabolic activity of S. aureus biofilm by 90% after 24 h of exposure. Darkening of tigecycline did not decrease antimicrobial activity of the lock solution or change the anticoagulant activity of heparin.

Although the optimal time for replacing an antimicrobial lock solution remains to be answered, we are moving in that direction showing that a highly concentrated tigecycline lock solution is a therapeutic alternative for Gram-positive long-term CRBSI lock treatment that can be safely used and replaced every 7 days. Further studies are needed to prove efficacy against other microorganisms, such as CoNS.

CITATION  J Antimicrob Chemother. 2016 Jan;71(1):278-9. doi: 10.1093/jac/dkv295. Epub 2015 Sep 22