The Multidrug-Resistant Gram-negative Superbugs Threat Require Intelligent Use of the Last Weapon

Abstract

The global emergence and dissemination of multidrug-resistant Gram-negative superbugs, particularly carbapenem-resistant Acinetobacter baumannii and Klebsiella pneumoniae, lead to the limited effectiveness of antibiotics for treating nosocomial infections. In most cases, polymyxins are the last resort therapy, and these antibiotics must be used intelligently to prolong their efficacy in clinical practice. Polymyxin B and colistin (polymyxin E) were introduced prior to modern drug regulation, and the majority of the 'old' drug information is unreliable. Recent pharmacokinetic data do not support the renal dose adjustment of intravenous (IV) polymyxin B as suggested by the manufacturer, and this drug must be scaled by the total body weight. Whereas IV colistin is formulated as an inactive prodrug, colistin methanesulfonate (CMS) has different pharmacokinetic profiles than polymyxin B. To achieve maximum efficacy, CMS should be administered as a loading dose scaled to body weight and a maintenance dose according to the renal profiles. Polymyxin combination therapy is suggested due to a sub-therapeutic plasma concentration in a significant proportion of patients and a high incidence of polymyxin hetero-resistance among Gram-negative superbugs. In conclusion, polymyxins must be reserved as a last resort and should be wisely used when truly indicated.

Keywords: Acinetobacter baumannii; Gram-negative; Klebsiella pneumoniae; colistin; polymyxin B.

Figure 1

The increasing trend of imipenem-resistance among Klebsiella pneumoniae (A) and Acinetobacter baumnannii (B) isolates from clinical specimens in the US ( ) and Hospital USM ( ). The US data were plotted based on data of K. pneumoniae (3) and A. baumannii (4), whereas the Hospital USM were data from Infection Control and Hospital Epidemiology Unit.

Figure 2

Global spread of bla_NDM-1 from 1 December 2009–31 December 2012. The figure is reproduced from (7).

Figure 3

New antibiotics approved in the United States, 1983–2012. The two last antibiotics from new classes were linezolid and daptomycin; both of them target against Gram-positive bacteria. The figure is reproduced from Infectious Diseases Society of America report (21).

Figure 4

Chemical structure of polymyxin B and colistin. In polymyxin B, D-Phe (phenylalanine) replaces the D-Leu (leucine) marked (red words). Colistin methanesulfonate (CMS) is produced by the reaction of colistin with formaldehyde and sodium bisulphite, which leads to the addition of a sulphomethyl group (SO₃CH₂) to the primary amines (NH₂) of colistin. Dab, α,γ-diaminobutyric acid, Thr, threonine. Modified from (22).