Background
In critically ill patients, the use of high tigecycline dosages (HD TGC) (200 mg/day) has been recently increasing but few pharmacokinetic/pharmacodynamic (PK/PD) data are available. We designed a prospective observational study to describe the PK/PD profile of HD TGC in a cohort of critically ill patients with severe infections.
Patients and study design
This was a single centre study that was conducted in the 20-bed mixed ICU of a 1500-bed teaching hospital in Rome, Italy. In all patients admitted to the ICU who received TGC (200 mg loading dose, then 100 mg q12) for the treatment of documented infections, serial blood samples were collected to measure steady-state TGC concentrations. Moreover, epithelial lining fluid (ELF) concentrations were determined in patients with nosocomial pneumonia.
Results
Amongst the 32 non-obese patients included, 11 had a treatment failure, whilst the other 21 subjects successfully eradicated the infection.
Pharmacokinetic results
In nosocomial pneumonia, for a target AUC0-24/MIC of 4.5, 75% of the patients would be successfully treated in presence of 0.5 mcg/mL MIC value and all the patients obtained the PK target with MIC ≤ 0.12 mcg/mL. In intra-abdominal infections (IAI), for a target AUC0-24/MIC of 6.96, at least 50% of the patients would be adequately treated against bacteria with MIC ≤ 0.5 mcg/mL. Finally, in skin and soft-tissue infections (SSTI), for a target AUC0-24/MIC of 17.9 only 25% of the patients obtained the PK target at MIC values of 0.5 mcg/mL and less than 10% were adequately treated against germs with MIC value ≥ 1 mcg/mL (Fig 1).
Pulmonary concentrations
Tigecycline pulmonary concentrations were measured in 12 (1 h) and 7 (12 h) patients, respectively. Main reasons to exclude samples were presence of blood and excessive dilution, whilst five patients did not undergo BAL due to severe respiratory failure. Mean ± SE ELF concentrations were similar at 1 h and 12 h (0.78 ± 0.2 mcg/mL vs. 0.36 ± 0.1 mcg/mL; p = 0.19). HD TGC showed a relevant pulmonary penetration with a median and IQR ELF/plasma ratio (%) of 152.9 [73.5–386.8] (Fig 2).
Conclusions
The study shows an HD TGC (200 mg LD, then 100 mg q12) time–curve concentration with mean peak and trough levels of 0.65 mcg/mL and 0.25 mcg/mL, respectively. AUC0-24/MIC targets for nosocomial pneumonia (≥ 4.5) and complicated intra-abdominal infections (≥ 6.96) were obtained in the majority of cases in presence of bacteria with MIC values ≤ 0.25. This dosage regimen was associated with a 65.6% of treatment success rate in a normal weight population including 60% of VAP, 31% of cIAI and 9% of SSTI. TGC was used in half of the cases as a targeted regimen for a median duration of 12 days. The use of HD TGC is associated with satisfactory plasmatic and pulmonary concentrations for the treatment of severe infections due to fully susceptible bacteria (MIC < 0.5 mcg/mL). Even higher dosages and combination strategies may be suggested in presence of difficult to treat pathogens, especially in case of SSTI and IAI.
Source: De Pascale, G., Lisi, L., Ciotti, G.M.P. et al. Pharmacokinetics of high-dose tigecycline in critically ill patients with severe infections. Ann. Intensive Care 10, 94 (2020). https://doi.org/10.1186/s13613-020-00715-2
