Acinetobacter baumannii has emerged as a highly troublesome pathogen for many institutions globally. As a consequence of its immense ability to acquire or upregulate antibiotic drug resistance determinants, it has justifiably been propelled to the forefront of scientific attention. Apart from its predilection for the seriously ill within intensive care units, A. baumannii has more recently caused a range of infectious syndromes in military personnel injured in the Iraq and Afghanistan conflicts. This review details the significant advances that have been made in our understanding of this remarkable organism over the last 10 years, including current taxonomy and species identification, issues with susceptibility testing, mechanisms of antibiotic resistance, global epidemiology, clinical impact of infection, host-pathogen interactions, and infection control and therapeutic considerations.

Acinetobacter baumannii: Emergence of a Successful Pathogen

Photodynamic therapy (PDT) employs a non-toxic dye, termed a photosensitizer (PS), and low intensity visible light which, in the presence of oxygen, combine to produce cytotoxic species. PDT has the advantage of dual selectivity, in that the PS can be targeted to its destination cell or tissue and, in addition, the illumination can be spatially directed to the lesion. PDT has previously been used to kill pathogenic microorganisms in vitro, but its use to treat infections in animal models or patients has not, as yet, been much developed. It is known that Gram-(−) bacteria are resistant to PDT with many commonly used PS that will readily lead to phototoxicity in Gram-(+) species, and that PS bearing a cationic charge or the use of agents that increase the permeability of the outer membrane will increase the efficacy of killing Gram-(−) organisms. All the available evidence suggests that multi-antibiotic resistant strains are as easily killed by PDT as naive strains, and that bacteria will not readily develop resistance to PDT. Treatment of localized infections with PDT requires selectivity of the PS for microbes over host cells, delivery of the PS into the infected area and the ability to effectively illuminate the lesion. Recently, there have been reports of PDT used to treat infections in selected animal models and some clinical trials: mainly for viral lesions, but also for acne, gastric infection by Helicobacter pylori and brain abcesses. Possible future clinical applications include infections in wounds and burns, rapidly spreading and intractable soft-tissue infections and abscesses, infections in body cavities such as the mouth, ear, nasal sinus, bladder and stomach, and surface infections of the cornea and skin.

Photodynamic therapy: a new antimicrobial approach to infectious disease?

Agents that increase the permeability of the outer membrane.

Outer Membrane Permeability and Antibiotic Resistance

Increasing multidrug resistance in Gram-negative bacteria, in particular Pseudomonas aeruginosa, Acinetobacter baumannii, and Klebsiella pneumoniae, presents a critical problem. Limited therapeutic options have forced infectious disease clinicians and microbiologists to reappraise the clinical application of colistin, a polymyxin antibiotic discovered more than 50 years ago. We summarise recent progress in understanding the complex chemistry, pharmacokinetics, and pharmacodynamics of colistin, the interplay between these three aspects, and their effect on the clinical use of this important antibiotic. Recent clinical findings are reviewed, focusing on evaluation of efficacy, emerging resistance, potential toxicities, and combination therapy. In the battle against rapidly emerging bacterial resistance we can no longer rely entirely on the discovery of new antibiotics; we must also pursue rational approaches to the use of older antibiotics such as colistin.

/pdf/colistin-the-re-emerging-antibiotic-for-multidrug-resistant-300sgudeer.pdf

Colistin: the re-emerging antibiotic for multidrug-resistant Gram-negative bacterial infections

Antibiotics taken up into gram-negative bacteria face two major diffusion barriers, the outer and cytoplasmic membranes. Of these, the former has been most studied and is discussed in detail here. Evidence from antibiotic MIC studies on porin-deficient mutants compared with their porin-sufficient parent strains has provided strong support for the proposal that some antibiotics, particularly β-lactams, pass across the outer membrane through the water-filled channels of a class of proteins called porins. Nevertheless substantial evidence has accumulated for the importance of non-porin pathways of antibiotic uptake across the outer membranes of gram-negative bacteria. Examples discussed include the uptake of polycationic antibiotics via the self-promoted pathway, the uptake of hydrophobic antibiotics in some bacterial species and in mutants of others via the hydrophobic pathway, and the possible importance of poorly understood non-porin pathways of uptake of a variety of antibiotics. Other potential barriers to diffusion, including the cytoplasmic membrane, are briefly discussed.

Antibiotic Uptake into Gram-Negative Bacteria

A novel artemisinin-quinine hybrid with potent antimalarial activity.

Malaria continues to devastate much of the tropics and sub-tropics in spite of the availability of a number of antimalarial drugs. Part of this problem is due to the disadvantages of the drugs in use, which include (depending on the drug) side effects, reduced efficacy due to resistance, and high cost. Multiple traditional and novel approaches to the discovery and design of new antimalarial agents are likely to be required to furnish the new drugs necessary for improved malaria control. This review will address one novel and emerging approach, namely the development of hybrid antimalarial agents composed of two distinct antimalarial moieties joined covalently. Particular emphasis will be placed on the properties of the hybrids' design, including biological activity, advantages over other approaches, and the potential to address issues relating to resistance, solubility and formulation/delivery. The review will discuss the synthetic methodology used to form the hybrid and the ease by which it may be cleaved to form the independent components in vivo. The molecules discussed include hybrids of (i) artemisinins or other endoperoxide-based agents and quinolines (e.g. trioxaquines), (ii) chloroquine or other aminoquinolines and resistance-reversing or other agents, and (iii) peptidase inhibitors and other agents. The actual and potential advantages and disadvantages of such hybrids in relation to established single drugs or drug combinations will be discussed critically and promising future directions highlighted.

Hybrid Drugs for Malaria

Interactions between antimicrobial agents provide clues as to their mechanisms of action and influence the combinations chosen for therapy of infectious diseases. In the treatment of malaria, combinations of drugs, in many cases acting synergistically, are increasingly important in view of the frequency of resistance to single agents. The study of antimalarial drug interactions is therefore of great significance to both treatment and research. It is therefore worrying that the analysis of drug-interaction data is often inadequate, leading in some cases to dubious conclusions about synergism or antagonism. Furthermore, making mechanistic deductions from drug-interaction data is not straightforward and of the many reported instances of antimalarial synergism or antagonism, few have been fully explained biochemically. This review discusses recent findings on antimalarial drug interactions and some pitfalls in their analysis and interpretation. The conclusions are likely to have relevance to other antimicrobial agents.

Antimalarial drug synergism and antagonism: mechanistic and clinical significance.

Peptidyl-prolyl cis-trans isomerases (immunophilins) and their roles in parasite biochemistry, host-parasite interaction and antiparasitic drug action.

Angus Bell

Papers

Antibiotic Uptake into Gram-Negative Bacteria

A novel artemisinin-quinine hybrid with potent antimalarial activity.

Hybrid Drugs for Malaria

Antimalarial drug synergism and antagonism: mechanistic and clinical significance.

Peptidyl-prolyl cis-trans isomerases (immunophilins) and their roles in parasite biochemistry, host-parasite interaction and antiparasitic drug action.