According to the Centers for Disease Control and Prevention and the Infectious Disease Society of America, each year in the USA alone, at least 2 million people are infected with bacteria that are resistant to antibiotics and more than 100,000 people are at risk of mortality each year as a direct result of these infections. With a reduced antibiotic pipeline in the pharmaceutical industry the dawn of the post-antibiotic era may be upon us with the arrival and widespread dissemination of extremely antibiotic resistant and pan-drug resistant bacteria. That said, new and old alternatives to antibiotics such as phage are under development to counteract pathogenic bacteria.
Gastrointestinal Klebsiella pneumoniae accounts for around a third of all Gram-negative infections, which can be hospital acquired or in the community. Strains that lack the outer membrane porins OmpK35 and OmpK36, which allow passive diffusion of small hydrophilic molecules, exhibit antibiotic resistance. K. pneumoniae also produces β-lactamases creating resistance to β-lactam antibiotics such as penicillins, cephalosporins, cephamycins, and carbapenems.
Ceftaroline, is a novel cephalosporin antibiotic. Avibactam is a potent, broad spectrum β-lactamase inhibitor. Jonathan R. Iredell and colleagues from The Westmead Institute for Medical Research including Westmead Biobank, New South Wales, Australia, investigated the effect of altered porin mediated outer membrane permeability alone and together with engineered β-lactamase enzyme mutations on antibiotic susceptibility of K. pneumoniae. The study using sixty-five banked bacterial strains was published in the International Journal of Infectious Diseases.
Ceftaroline showed potent activity against K. pneumoniae ATCC 13883 and all the mutant porin strains including double deletion mutants with a minimum inhibitory concentration (MIC) range of 0.125-0.25 µg/ml. Avibactam improved antibiotic potency in strains carrying extended spectrum beta lactamase enzymes, however the presence of OmpK35 mutation reduced this improved efficacy by four-fold.
Only four clinical isolates with OmpK35 and OmpK36 porin defects and carrying multiple beta lactamases and carbapenemases had raised MICs against ceftaroline/avibactam, 86% were successfully inhibited despite the porin defects and β-lactamases.
“In conclusion, the results of this study demonstrated that the combination of avibactam at 4µg/ml with ceftaroline exponentially expands its spectrum of activity to cover the highly resistant organisms with multiple β-lactamases and serine carbapenemases commonly present in porin defective clinical isolates of K. pneumoniae. It is clear that permeation is an important barrier dictating the efficacy of this drug combination. However, avibactam diffusion into the bacteria was not influenced by the presence of different porin alterations, consistent with earlier findings, making this drug combination a potentially effective therapeutic agent to treat infections caused by multidrug-resistant bacteria with permeability defects,” stated the authors.