Bacterial resistance to antibiotic therapies is a global crisis that recently prompted the World Health Organisation (WHO) to publish its first ever list of pathogens considered to be a priority for the threat they pose to human health. Among the 12 pathogens singled out, a virulent bacterium named Pseudomonas Aeruginosa was among three considered to be critical in terms of need for new therapies to combat this killer. A new strategy to fight these often fatal infections has emerged in the form of combination therapies, where a parent drug capable of neutralising the harmful bacteria is paired with an agent that can either protect the active molecule from bacterial resistance tricks, or else can facilitate the penetration of the second agent into the bacterial cell so the neutralising molecule can go to work. Many of these promising new agents are still in pre-clinical stages, and some are moving through clinical trials. In other words, few are ready and approved for prime time use in intensive care units (ICUs) where patients are suffering.
Overcoming the defenses through combined efforts
A clinical pharmacist specialising in infectious diseases at Sinai-Grace Hospital in Detroit, Michigan, Jason Pogue, Pharm.D, set out to learn where one of the more promising newer agents is actually being used in the clinic and the effectiveness of its use. Randomised controlled trials of the combination of the parent drug ceftolozane with an inhibitor agent tazobactam, in target populations, will ultimately answer the question of efficacy for clinicians, he said. Ahead of that key piece of evidence, Pogue said a description of real-world utilisation is helpful to describe for clinicians what has been done in clinical practice as a supplement to clinical trial data.
At the 2017 European Congress of Clinical Microbiology and Infectious Diseases, held in Vienna this April, Pogue presented a poster including 293 patients receiving the ceftolozane-tazobactam therapy who were identified through an electronic research database of 315 hospitals in the United States maintained by the Becton Dickinson Company. The study was supported by Merck & Co., which manufactures the ceftolozane-tazobactam combination therapy under the brand name Zerbaxa. Among the 293 patients there were 314 treatments, most often started in the ICU and most often to treat respiratory tract infections. The most common pathogen was Pseudomonas Aeruginosa, which was isolated in 241 cases or 77% of the combination courses of treatment. The conclusion for the study remains necessarily inconclusive as to the effectiveness of treatment, Pogue said. Instead the data is descriptive of how the therapy is being applied, particularly as these data show the agent is being used outside of the labelled indication in nearly half the cases.
In a next step, the pharmacist said, the study lends itself to a comparison to patient populations who received other therapies for the same type of conditions identified in the ceftolozane-tazobactam study, bringing clinicians closer to the efficacy question ahead of the results from clinical trials, and as a complement to those trial results once published. ‘As these data show, the primary use of ceftolozane/tazobactam in the clinic is for respiratory tract infections with Pseudomonas Aeruginosa. However, the published evidence to support this is very limited. Approval of this combination was granted on the basis of efficacy against specific disease states (urinary tract infections and intra abdominal infections), not against a pathogen. Yet, because thankfully these resistant organisms are relatively rare, there is unfortunately a lower likelihood they will be encountered in a registry trial for drug approval. The clinical concern for drug resistant P. aeruginosa is in the respiratory tract where, as stated, data are currently lacking,’ he said.
Different strategies to preserve effectiveness of antibiotics
Right now we are working hard to find that sweet spot for optimal treatmentJason Pogue
‘What we found through our analysis is that the primary use of ceftolozane/tazobactam appears to be for Pseudomonas Aeruginosa in patients with nosocomial pneumonia and, while the combination drug is not approved for that indication, though a trial has been started, in the real world of clinical practice the treatment is being used in the ICU. Again, the point is not to say this combination works but instead to describe where clinicians have utilised it,’ Pogue said. Awaiting wider approval for new agents against the pathogens identified by the WHO, Pogue said clinicians apply different strategies to preserve the effectiveness of the antibiotics that are available.
Pogue is an advocate of an approach called stewardship that centres on reserving antibiotics so that the pathogen does not learn to resist them. The four tenets of antibiotic stewardship consist of giving patients the right drug in the right dose with the right delivery method and, according to Pogue, most importantly, for the right duration of treatment, neither too short nor too long. ‘For most diseases caused by infections there is good evidence that significantly shorter therapy durations are probably sufficient. Right now we are working hard to find that sweet spot for optimal treatment, finding the low end of the duration that matches with efficacy,’ he said.
Dr Jason Pogue is an infectious diseases clinical pharmacist at Sinai-Grace Hospital in Detroit, MI. He also serves as an assistant clinical professor of medicine at the Wayne State University School of Medicine. He received a bachelor degree in Chemistry from Gannon University before obtaining his doctor of pharmacy degree from the University of Pittsburgh. He then completed a PGY-1 residency at the University of Pittsburgh Medical Centre, after which he left Pennsylvania for Michigan to obtain his PGY-2 ID training at the University of Michigan Health Systems. His research interests focus on epidemiology and treatment of multi-drug resistant Gram-negative organisms and antimicrobial stewardship, and he has co-authored over 70 peer reviewed articles, 100 abstracts at national and international meetings and multiple book chapters in these areas. Pogue was recently invited to become an advisor for USCAST, an organisation that aims to standardise antimicrobial susceptibility breakpoints in the USA.