A Randomised Controlled Trial Evaluating a Novel Individualised Treatment Strategy for Carbapenem-Resistant Gram-Negative Bacteria Infections (iACT)

The health problem - Antimicrobial resistance (AMR) in GNB and the dearth of therapeutic options AMR, particularly in GNB infections (e.g. Pseudomonas aeruginosa, Enterobacteriaceae and Acinetobacter baumannii), means resistance to multiple or even all available antibiotic classes. The growing incidence of CRGNB and XDRGNB is an urgent global healthcare challenge today. These pathogens are classified as "priority 1" (utmost critical) pathogens by the World Health Organization (WHO). Hsu et al from Singapore has published recently on the estimated prevalence of carbapenem-resistant Enterobacteriaceae (CRE) and carbapenem-resistant A. baumannii (CRA).

Antibiotics are the "foundation" of modern medicine, without which key medical procedures including surgery and chemotherapy for cancer are rendered too dangerous to perform. With the advent of CRGNB, effective antibiotic treatment strategies are now limited. Currently, approximately 700,000 people die from resistant infections every year in the world. It is estimated that by 2050, 10 million lives (1 in 3 The people) per year and a cumulative USD $100 trillion of economic output are at risk due to drug resistant infections, if resistance rates continue to rise unabated. Patel and co-workers observed mortality rates of 40-50% in patients with bloodstream infections caused by CR Klebsiella pneumoniae. Most CRE infections and the transmission of CRE are predominantly linked with healthcare exposure.

Combination therapy - a current mainstay therapeutic option against CRGNB Given the current resistance landscape, coupled with a continued dwindling pipeline of drugs to treat these infections, physicians in Singapore now face a severe lack of effective antimicrobial therapies to treat infections caused by CRGNB. While polymyxin B, an old antibiotic previously forsaken due to an allegedly high rate of toxicities, has been resurrected for such infections, the presence of polymyxin B heteroresistance limits its utility as a monotherapy in severe or deep-seated infections. Currently, antibiotic combination therapy has been adopted by most infectious diseases (ID) physicians locally, as the mainstay treatment against CRGNB infections, because of the theoretical benefits conferred by antibiotic combination therapy (e.g. synergism, prevention of development of resistance). In addition, there is increasing clinical evidence suggesting that antibiotic combination therapy may improve prognosis.

Unfortunately to date, the mortality reduction associated with antibiotic combination therapy in the treatment of CRGNB infections has not been consistently observed across all studies. For example, in a prospective comparison of 55 patients treated for XDR A. baumannii infections, the authors found that the combination of colistin + tigecycline resulted in higher mortality than colistin + a carbapenem when the tigecycline minimum inhibitory concentration (MIC) of the causative pathogen was >2 mg/L (HR = 6.93, 95% CI 1.61-29.78; P= 0.009), suggesting that caution is needed when developing polymyxin combination regimens.

In our local retrospective study, the Investigators have shown that when compared to polymyxins monotherapy or unguided antibiotic combination therapy, the guided selection of a rationally optimised antibiotic combinations was associated with significantly lower rates (by 8 times) of infection-related mortality in patients with XDRGNB infections. In most previous combination therapy studies in the clinical setting, the studies are typically limited by small sample sizes and retrospective nature. To address the ambiguity surrounding the use of polymyxin combinations, three large prospective RCTs are currently underway in Europe and the USA (ClinicalTrials.gov IDs NCT01732250, NCT0159797, NCT03159078)). In these trials, a fixed combination (polymyxins + carbapenem) will be compared to a fixed type of monotherapy (polymyxins alone).