A Review of Novel Combinations of Colistin and Lipopeptide or Glycopeptide Antibiotics for the Treatment of Multidrug-Resistant Acinetobacter baumannii

As antibiotic resistance continues to increase among Gram-negative organisms such as Acinetobacter baumannii there is a growing need for novel therapies to overcome these resistance mechanisms. Antibiotics active against multidrug-resistant A. baumannii (MDRAB) are few, and agents in development are primarily active against other multidrug-resistant Gram-negative organisms. The combinations of colistin and antimicrobials such as glycopeptides and lipopeptides are unique potential treatment modalities against MDRAB. For both lipopeptides and glycopeptides in vitro data have demonstrated significant synergy, resulting in rapid bactericidal activity in time-kill curves. Several invertebrate in vivo models have also demonstrated increased survival compared to colistin alone. Currently, very little clinical data have focused on using these combinations for infections caused exclusively by multidrug-resistant Gram-negatives. The combination of vancomycin and colistin has been studied with conflicting results regarding both improved outcomes and risk of nephrotoxicity. Although in vitro and in vivo models have proved promising, further investigation is required to provide clinical data necessary to support the use of these combinations. The objective of this review is to summarize literature currently available for the novel combination of lipopeptides or glycopeptides with colistin for the treatment of A. baumannii, in particular MDRAB. Electronic supplementary material The online version of this article (doi:10.1007/s40121-014-0051-9) contains supplementary material, which is available to authorized users.


INTRODUCTION
Antibiotic resistance continues to be a global public health crisis [1]. The Centers for Disease Control and Prevention (CDC) state that resistant bacteria cause over two million infections in the United States annually, with a mortality rate of over 20,000 individuals per year [2,3]. Curtailing resistance through infection control measures is key to mitigating the threat and decreasing the spread of these organisms [4]. Once patients are infected, however, optimizing antimicrobial therapy becomes paramount. This is a challenge secondary to the declining availability of active agents and dwindling pipeline of novel  [19][20][21][22]. This review will focus on several unconventional combinations with colistin that have demonstrated possible clinical utility.

METHODS
Literature associated with the combination of colistin and glycopeptides, lipopeptides, and lipoglycopeptides for the targeted treated of ACB was included in this review. All relevant English-language peer-reviewed publications were accessed through PUBMED using the following medical subject heading (MeSH) terms: vancomycin, daptomycin, telavancin, glycopeptide, lipopeptide, lipoglycopeptide, colistin, Acinetobacter baumannii, and combination therapy. Citations within these references were also assessed for inclusion. Publications in abstract form were included in the review if these abstracts were presented as part of professional meetings.
The analysis in this article is based on previously conducted studies and does not involve any new studies of human or animal subjects performed by any of the authors.

Studies with Glycopeptide Antibiotics
Until recently little was known about combinations of colistin and antimicrobials with exclusive activity against Gram-positive bacteria. Novel combinations of colistin plus glycopeptide and lipopeptide antibiotics have recently been examined, yielding positive results [23,24]. Vancomycin is a glycopeptide antibiotic that has become a mainstay in the treatment of methicillin-resistant Staphylococcus aureus (MRSA) over the past two decades that works by inhibiting peptidoglycan synthesis in the bacterial cell wall [25,26]. The proposed mechanism of synergy relates to the cellmembrane permeabilizing ability of colistin.
Colistin causes an electrostatic interaction with LPS (lipid A), disrupting the outer membrane of the Gram-negative bacteria. This allows the otherwise large and hydrophobic vancomycin molecules to pass through the outer LPS layer and reach the site of action at the cell wall [23,24].
Synergy between vancomycin and colistin in MDRAB was first described by Gordon  Gram-positive co-infection (41.2% versus 0.0%, p\0.001). Thirty-day mortality was not significantly different between those treated with the combination and those treated with monotherapy (33.8% versus 29.6%). Although infection with MDRAB was an independent predictor of mortality, through cox regression the receipt of the combination for C5 days was shown to be protective for 30-day survival.
There was no difference in renal toxicity between the patients who received glycopeptides and those that did not.

Studies with Lipopeptide Antibiotics
In addition to the glycopeptides, the lipopeptide antibiotic daptomycin and lipoglycopeptide antibiotic telavancin have been investigated in combination with colistin (Table 1). Telavancin has a dual mechanism of action wherein it acts as glycopeptide antibiotics by inhibiting transpeptidation and transglycosylation, the peptidoglycan polymerization step of cell wall synthesis, as well as altering cell membrane permeability via changing membrane potential [35,36]. Similar to vancomycin and teicoplanin, the combination with colistin has demonstrated significant synergy in vitro and improved survival in an in vivo invertebrate model [30,37]. Daptomycin has a unique and not yet fully elucidated mechanism of action that causes calcium-dependent destabilization of the cell membrane as well as altering the cell wall through septal defects [38]. As is the case with glycopeptides, the presence of a LPS outer membrane in Gram-negative bacteria protects against daptomycin binding to the cellular membrane.  isolates that were exposed to 0.5 9 MIC colistin bactericidal activity occurred in five (50%), compared to zero isolates exposed without daptomycin. Nine of 10 isolates exposed to colistin at 1 9 MIC demonstrated bactericidal activity with no regrowth at 24 h. It appears the possible benefits of the daptomycin-colistin  impact of these combinations is required to determine the possible benefits associated with use of such combinations. In particular, elucidation of the mechanism by which these combinations seem to work best in ACB as opposed to other MDR Gram-negative pathogens and further investigation of whether higher doses of daptomycin will improve results in MDRAB [24,40,41].
Additionally, further description of use of these combinations in monomicrobial MDRAB infections without de-escalation to colistin monotherapy following eradication of coinfecting Gram-positive pathogens would be beneficial from a clinical perspective. It is also unclear if utilizing polymyxin B in lieu of colistin would provide similar synergistic activity against ACB or other MDR Gramnegative pathogens. Lastly, triple therapy with colistin, a lipopeptide or glycopeptide, and another agent active against MDRAB such as tigecycline or carbapenems should also be investigated in the clinical setting. With a dwindling pipeline of agents with novel mechanisms of action, finding new and unique means to employ antibiotics that are currently available is crucial to improve outcomes in these life-threatening infections.