Aridis Pharmaceuticals, San Jose, CA. drug-resistant (XDR) or pandrug-resistant (PDR) (2). Carbapenem resistance rates exceed 90% in some parts of the world (3), and mortality rates for the most common CRAB infections, i.e., hospital-acquired pneumonia (HAP) and bloodstream infections (BSI), may approach 60% (4). This is significantly higher than rates for carbapenem-susceptible infections (5). Current antimicrobials for CRAB (i.e., polymyxins, tigecycline, and sometimes aminoglycosides) are far from perfect therapeutic options due to their pharmacokinetic properties and increasing resistance rates. In these dire circumstances, the need for new therapeutic options for the treatment of CRAB infections is indisputable. Since antimicrobial discovery and resistance development to the new antimicrobial are nearly simultaneous, drugs with novel mechanisms of action that will overcome current resistance mechanisms are sought after. Currently, there are a small number of drug candidates and other therapeutic options that may meet those expectations. This review will focus on such drugs that are in clinical or late preclinical studies (Table 1). In addition, phage therapy and monoclonal antibodies for CRAB will be evaluated. The purpose of this review is to describe the state of anti-CRAB therapies by providing an overall picture of the current pipeline. As all antimicrobials face the eventual fate of being defeated by the bacteria, possible resistance mechanisms against new therapies will also be evaluated. This review is expected to guide the development of new and better drugs and to inspire further novel therapeutic options against resistant microorganisms. TABLE 1 New therapeutic options activity against strains; however, they suffer from a lack of clinically relevant susceptibility breakpoints, very narrow therapeutic spectrum, and serious side effects of nephrotoxicity and neurotoxicity (6). Resistance emerging during therapy due to colistin-heteroresistant strains and difficulty in determining heteroresistance are other important issues that may result in unfavorable clinical outcomes (7). With an undefined optimal dosing, high toxicity, and increasing resistance (7,C9), polymyxin-based therapies are far from being safe KN-92 hydrochloride and effective for the treatment of CRAB infections (Table 2). TABLE 2 Limitations of current therapeutic options =?0.171). Until the results of a large well-designed double-blind randomized trial comparing the colistin-carbapenem combination versus colistin monotherapy (14) are available, it may still be considered that the question of combination therapy is not definitively answered. Tigecycline, developed for the treatment of multidrug-resistant (MDR) pathogens and having potent activity against activity against CRAB. It is the only agent against CRAB which can be administered by the oral route. High susceptibility rates (72.1% in the United States and 81.4% in Thailand) were shown in some studies (21), although resistant strains are not infrequent (22, 23). Lashinsky et al. recently reviewed seven retrospective studies which evaluated the Rabbit Polyclonal to IKK-gamma (phospho-Ser31) use of minocycline alone or in combination with other agents against MDR infections and found high clinical and microbiological success rates (78.2% and 50% to 89%, respectively) (21). However, one should be cautious while interpreting the results of this review, since there were only 126 patients, 94 of whom were treated with combination therapy, and most patients (74.6%) suffered from respiratory KN-92 hydrochloride tract infections. A new intravenous formulation of minocycline was placed in the U.S. market in 2015, and a pharmacokinetic study (Acute Care Unit KN-92 hydrochloride MINocycline [ACUMIN]) to determine optimal dosing for the critically ill is ongoing (24). Although high susceptibility rates in some series and good safety profile are encouraging, minocyclines role as an anti-CRAB agent needs further investigation. Amikacin is another drug used as an anti-CRAB agent because it retains activity against some strains. However, its nephrotoxicity and high resistance rates (68% to 100%) limit its systemic use (3). A large RCT comparing inhaled amikacin as adjunctive therapy to the standard of care in VAP patients failed to demonstrate its superiority over the standard of care and a placebo (25). Sulbactam is a -lactamase inhibitor with intrinsic activity against (33). NEW THERAPEUTIC OPTIONS Siderophore cephalosporins. (i) Cefiderocol. Cefiderocol (S-649266) KN-92 hydrochloride is a recently developed novel cephalosporin conjugated with a catechol siderophore on its side chain. Cefiderocol has a distinctive active uptake mechanism and stability against many -lactamase classes, which provide enhanced penetration of bacterial cell and activity against highly resistant Gram-negative bacteria, including CRAB (34). In studies, cefiderocol was shown to be potent against OXA-23, KN-92 hydrochloride OXA-40, and OXA-58 as well as NDM- and IMP-producing isolates, with MIC90s ranging from 1 to 8?g/ml (35,C40). However, it seems to be less active against some strains of that express OXA-23 and OXA-40 (38, 40, 41). Characterization of the carbapenemases of CRAB strains from.