Multidrug-resistant Gram-negative infections: what are the treatment options?

The emergence of multidrug-resistant (MDR) Gram-negative bacilli creates a challenge in the treatment of nosocomial infections. While the pharmaceutical pipeline is waning, two revived old antibacterials (colistin and fosfomycin), a newer one (tigecycline) and an 'improved' member of an existing class (doripenem) are the only therapeutic options left. The class of polymyxins, known since 1947 and represented mostly by polymyxin B and polymyxin E (colistin), has recently gained a principal role in the treatment of the most problematic MDR Gram-negative pathogens (such as Pseudomonas aeruginosa, Acinetobacter baumannii, Klebsiella pneumoniae and Stenotrophomonas maltophilia). Future prospective studies are needed to answer important clinical questions, such as the possible benefit of combination with other antimicrobials versus monotherapy, the efficacy of colistin in neutropenic hosts and the role of inhaled colistin. As new pharmacokinetic data emerge, clarification of the pharmacokinetic/pharmacodynamic (PK/PD) profile of colistin as well as appropriate dosing seems urgent, while development of resistance must be carefully monitored. Fosfomycin tromethamine, a synthetic salt of fosfomycin discovered in 1969, has regained attention because of its in vitro activity against extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae and MDR P. aeruginosa. Although in use for decades in oral and parenteral formulations for a variety of infections without significant toxicity, its clinical utility in MDR infections remains to be explored in future studies. Tigecycline, the first representative of the new class of glycylcyclines, holds promise in infections from MDR K. pneumoniae (K. pneumoniae carbapenemase [KPC]- and ESBL-producing strains) and Enterobacteriaceae with various mechanisms of resistance. The in vitro activity of tigecycline against A. baumannii makes it a tempting option, as it is currently the most active compound against MDR strains along with colistin. However, the usual minimum inhibitory concentration values of this pathogen are approximately 2 mg/L and compromise clinical outcomes based on PK/PD issues. Its advantageous penetration into various tissues is useful in infections of the skin and soft tissues as well as intra-abdominal infections (official indications), whereas low serum concentrations compromise its use in bloodstream infections. Therefore, prospective studies with dose escalation are urgently needed, as well as clarification of its role in nosocomial pneumonia, after poor results in the study of ventilator-associated pneumonia. Finally, doripenem, the recently licensed member of the carbapenems (without significant spectrum alterations from the ascendant members) seems to possess a lower potential for resistance selection and a more favourable pharmacokinetic profile when given as an extended infusion. The latter strategy could prove helpful in overcoming low level resistance of A. baumannii and P. aeruginosa strains.