Combination Therapy for Carbapenem-resistant Gram-negative Bacteria

Alexandre P Zavascki; Jurgen B Bulitta; Cornelia B Landersdorfer


Expert Rev Anti Infect Ther. 2013;11(12):1333-1353. 

In This Article


Tigecycline is a minocycline derivative belonging to the new class of antimicrobials known as glycylcyclines.[134] It is a broad-spectrum antimicrobial with activity against many Gram-positive, Gram-negative and anaerobic pathogens and has been frequently prescribed as a part of combination schemes against CR Enterobacteriaceae and also CR A. baumannii.[48,135,136] Unfortunately, tigecycline is not active against P. aeruginosa.[134] Despite some differences in the reported susceptibility breakpoints of this drug (1 or 2 mg/l), it has been shown in many surveillance studies that tigecycline presents good in vitro activity against many MDR and XDR Enterobacteriaceae and A. baumannii isolates.[137,138]

Several meta-analyses of RCTs involving tigecycline versus comparators have shown that tigecycline therapy was associated with lower cure and higher mortality rates than comparators in patients treated with tigecycline.[139–142] Additionally, a RCT compared tigecycline (using the approved dose in the product label: 100 mg loading dose followed by 50 mg every 12 h) plus ceftazidime with imipenem-cilastatin plus vancomycin for the treatment of hospital-acquired pneumonia (HAP).[143] A significantly lower cure rate was found in the tigecycline group in the subset of patients with ventilator-associated pneumonia.[143] These studies discouraged the use of tigecycline alone for the treatment of severe infections, especially pneumonia. However, considering its in vitro activity against many CR Enterobacteriaceae and A. baumannii, tigecycline has been used as a part of combination schemes, usually as the adjuvant agent but also as the cornerstone treatment.[8,46,144]

The fAUC/MIC is the PK/PD index that best correlates with in vitro activity of tigecycline.[145] The tigecycline PK is characterized by low serum concentrations, frequently below the MIC of many GNB.[146] This fact has led many physicians to prescribe higher tigecycline doses in order to increase serum concentrations and optimize the AUC.[147,148] Considering the linearity of tigecycline PK, the AUC increases in proportion with increasing tigecycline doses.[149] Thus, a second RCT comparing two higher dosage regimens of tigecycline (150 mg followed by 75 mg every 12 h and 200 mg followed by 100 mg every 12 h) with imipenem/cilastatin in subjects with HAP was performed. It demonstrated that clinical response rates with the 100-mg dosage regimen were higher than with the 75 mg tigecycline dose and the imipenem/cilastatin control,[150] supporting the benefit of higher doses to improve clinical outcomes. Importantly, the safety profile of the higher doses was similar to the approved dose of tigecycline.[150]

To assess the PK/PD and patient-specific factors affecting clinical and microbiological outcomes, PK and clinical data retrieved from patients enrolled in the first RCT of tigecycline for the treatment of HAP were further analyzed.[145] Assuming an unbound fraction of tigecycline of 0.20, the authors found that a fAUC/MIC ≥0.90 and ≥0.35 were associated with higher clinical and microbiological response rates, respectively, suggesting that these values should be targeted when prescribing tigecycline, at least for pulmonary infections.[145] Thus, considering a protein binding of 80% and the mean AUC0–24h reached after a 100-mg dose,[151] a fAUC/MIC ≥0.90 against pathogens with an MIC for tigecycline of 0.5 and 1 mg/l will be more easily reached with the high dosage regimen. For MICs below 0.5 mg/l, the usual dose of 50 mg every 12 h may be appropriate for achieving an fAUC/MIC ≥0.90. In contrast, if the MIC is 2 mg/l (susceptibility breakpoint for Enterobacteriaceae according to the FDA), this target is unlikely to be reached.