High dose tigecycline in critically ill patients with severe infections due to multidrug-resistant bacteria

Tigecycline (TGC) is the first glycylcycline of the tetracycline antibiotic class approved in Europe for the treatment of complicated skin and skin-structures infections (cSSI), complicated intra-abdominal infections (cIAI), at a dose of 50 mg twice daily after a 100 mg loading dose,[ 1].

In vitro this antibiotic has shown good antibacterial activity against most of aerobic and anaerobic bacteria, including multidrug-resistant (MDR) Gram-negative bacteria. However Pseudomonas aeruginosa, Proteus spp. and Providencia spp. are intrinsically resistant[ 1].

A recent Food and Drug Administration (FDA) alert[ 2] announced an increased TGC-attributable mortality, thus discouraging its adoption for severe nosocomial infections. However, due to the scarcity of other effective antimicrobials its use is frequently extended to the treatment of colistin-resistant bacteria[ 3].

Because the area under the plasma concentration versus time (AUC) to microorganism minimal inhibitory concentration (MIC) ratio (AUC/MIC ratio) is the major determinant of antimicrobial activity of TGC, some authors have proposed increased daily dosages for treating severe infections due to MDR bacteria[ 4]. Clinical experience with doses >100 mg daily is very limited, but data reported to date suggest that TGC may be useful and well-tolerated at higher doses[ 5, 6].

Thus we performed a retrospective analysis of prospectively collected data from critically ill patients who received TGC for microbiologically confirmed severe infections, to investigate its efficacy and safety at higher than standard doses.

In this study we found that the use of HD TGC (100 mg every 12 hours following a 200 mg loading dose) was well-tolerated in a cohort of critically ill patients affected by nosocomial infections. In the VAP subgroup population (all episodes due to Gram-negative germs), the HD TGC was independently associated with a six-fold increase in clinical cure. Conversely an IIAT and a higher SOFA score were independent predictors of clinical failure. The association of increased TGC dosage and improved outcome is coherent with previous clinical observations regarding this and other molecules[ 4, 19, 20].

Recently, an HD TGC regimen has been successfully used in combination with other active antimicrobials in 22 critically ill patients with K. pneumoniae Carbapenemase-producing (KPC) K. pneumoniae infections (mainly VAP and BSI)[ 21]. The authors reported a high percentage of favorable response (88% clinical cure and 92% survival), probably due to the specific case mix of that population, represented by young trauma patients without significant comorbidities and septic shock.

TGC effectively penetrates skin, soft tissues and intra-abdominal organs but several concerns have been raised about its distribution in the lung. In a phase-3 trial[ 22] this molecule was compared with imipenem for the treatment of hospital-acquired pneumonia, without reaching non-inferiority criteria in the subset of patients with VAP. Moreover, some authors[ 23] have observed that TGC lung concentrations in intracellular epithelial lining fluid (ELF) were remarkably higher than in the extracellular fluid and serum. This observation has suggested the use of higher dosages in order to treat pneumonia caused by MDR pathogens. These data were also confirmed by a recent multicenter PK study in children affected by serious infections, where a dose of 1.2 mg/kg every 12 hours better correlated with the target AUC _0–24:MIC ₉₀ ratios[ 24]. Hence, although TGC lung levels in infected patients are expected to be higher than healthy volunteers, standard doses are probably inadequate to reach maximally efficacy, especially against MDR pathogens on the upper end of the MIC distribution (1 to 2 mcg/ml). Recently, in a randomized phase-2 trial, treatment with HD TGC (100 mg every 12 hours) was associated with a better clinical response than imipenem treated patients, in nosocomial pneumonia caused by Gram-positive and Gram-negative bacteria. This clinical result was supported by the favourable PK-PD profile observed in HD TGC treated patients[ 6].

Few other authors have reported the treatment of MDR severe infections with TGC at higher than standard doses. Cunha[ 25] described the successful use of this molecule, up to 200 mg every 24 hours, during urinary tract infection/urosepsis, reporting no adverse effects. Similarly Lewinski et al.[ 26] reported a case of PDR K. pneumoniae pneumonia and bacteremia resolved with a combination of colistin and HD TGC. In general, TGC use is associated with few significant AE other than nausea and vomiting[ 27, 28], but two recent meta-analyses documented that this molecule administration was associated with more AE than comparative drugs[ 29, 30]. Not surprisingly, the most frequently reported AE (nausea and vomiting) had no impact in our cohort of critically ill patients, who were sedated and mechanically ventilated. To date there are limited data for AE related to the use of HD TGC[ 25, 28]. In our cohort, the percentage of patients who manifested biochemical abnormalities, grading the AE, varied between 10% and 20%. Anyway, the retrospective design of this study does not allow an accurate estimation of the TGC contribution to these abnormalities. Hence, due to the high severity of our study patients, other factors might have exerted a crucial role affecting organ functions.

The overall ICU mortality observed in the entire cohort (100 patients) was high (57%) and only about half of patients achieved clinical cure or microbiological eradication (48% and 41%, respectively). These data might be explained by the relevant severity of illness: about 50% of them were in septic shock, 24% were receiving continuous renal replacement therapy (CRRT)and 35% had concomitant bacteremia. Recent reports suggest the usefulness of combination antimicrobial schemes including TGC, mainly during the treatment of KPC-producing K. pneumoniae infections[ 21, 31]. However, despite the combined antimicrobial therapy strategy we have adopted, the percentage of IIAT was high (49%), and possibly responsible for the relevant rate of the observed unfavorable outcomes[ 32].

In our institution the use of HD TGC constantly increased over the study period, concomitantly with the shift towards less susceptible bacteria (Figure  2). The trend to increase TGC dosage used was probably influenced by the awareness of progressive increase in TGC MIC values in MDR germs isolated in our hospital, with the aim to avoid suboptimal doses for the management of difficult-to-treat infections.

Our study has several limitations. First, this is a single-center, retrospective analysis with a relatively small number of patients. Second, in almost all the patient TGC was used in addition to another active molecule and therefore we cannot draw any conclusion regarding the efficacy of HD TGC as monotherapy. Finally, we did not monitor the plasmatic and tissue concentrations that could confirm our clinical observations. However, to our knowledge, this is the largest comparative clinical study where the use of HD TGC has been described.

These data suggest that TGC, used at doses higher than standard treatment, can be administered without relevant toxicity for the treatment of serious infections in critically ill sedated patients. The regimen with higher TGC doses (that is, 100 mg every 12 hours after a 200 mg loading dose) may be useful to improve the clinical outcome of patients with MDR Gram-negative VAP. Pharmacokinetic investigations and multicenter, prospective clinical trials are needed to confirm these preliminary results and investigate the efficacy of HD TGC in severe infections.