**8. Antibiotic resistance**

Worldwide, antibiotic resistance is a major contemporary public health threat due to rapid emergence of resistant bacteria and endangering the efficacy of antibiotics [17]. In 2014, the WHO warned that the antibiotic resistance crisis is becoming extremely serious [18] and is attributed to the overuse and misuse of these medications, as well as a lack of new drug development by the pharmaceutical industry [19]. Different molecular mechanisms are responsible for the development of antimicrobial resistance such as alteration of bacterial cell permeability, acquisition of extended spectrum β-lactamase production (ESBLs), and metalloβ-lactamases (MBLs), bacterial biofilm formation, activation of efflux pump, bacterial conjugation, and curli fiber formation [17, 20–25].

A few of such synergistic novel antimicrobial adjuvant entities, their mechanisms, and clinical outcomes, which can revolutionize the future, will be discussed in this book chapter. These AAEs have been developed for both Gram-positive and Gram-negative multidrug-resistant infections. Elores (ceftriaxone + sulbactam with adjuvant EDTA) and Potentox (cefepime + amikacin with adjuvant potassium chloride (KCl)) are the AAEs for Gram-negative MDR pathogens each catering to a different type of resistance, and Vancoplus (ceftriaxone + vancomycin with adjuvant L-arginine), another AAE, can help us to last longer in the war against antibiotic-resistant Gram-positive bugs particularly which cause complicated LRTI leading to

Advancing in the Direction of Right Solutions: Treating Multidrug-Resistant Pneumonia

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CSE1034 is a novel combination of third-generation cephalosporin "ceftriaxone," an irreversible β-lactamase inhibitor "sulbactam," and non-antibiotic adjuvant Antibiotic Resistance Breaker (ARB) "disodium edetate." Due to synergistic action of the inhibition of cell wall by ceftriaxone accompanied by the specific inhibition of β-lactamases by β-lactam component produced by common Gram-negative and Gram-positive pathogens, this drug has been reported to be affective against multiple types of MDR organisms. CSE1034 has proven activity against a wide range of ESBL and MBL producing Gram-negative pathogens and is used

Ceftriaxone acts by binding to penicillin-binding proteins (PBPs) which are transpeptidases that catalyze the cross-linking of the peptidoglycan polymers synthesizing cell wall and subsequently inhibiting bacterial cell wall synthesis. The cell wall of bacteria consists of pentapeptide units attached to a polysaccharide backbone with alternating units of N-acetylglucosamine (NAG) and N-acetylmuramic acid (NAM). PBPs act on a terminal d-alanyl-d-alanine moiety on a pentapeptide unit and catalyze the formation of a peptide bond between the penultimate D-alanine and a glycine unit on an adjacent peptidoglycan strand. The ceftriaxone structure is the mimic of D-alanyl-D-alanine moiety and the PBPs wrongly attack the β-lactam ring in ceftriaxone, which leads to the inactivation of PBPs. As the peptidoglycan synthesis is essential to maintain bacterial cell wall integrity, so the inhibition of PBPs leads to damage and

Sulbactam is a potent, highly specific inhibitor of a wide variety of β-lactamases including penicillinases and cephalosporinases produced commonly by different strains of bacteria and chromosomally mediated enzymes induced in some strains of *Klebsiella, Enterobacter*, and *Serratia* species to degrade antibiotics. By forming a protein complex with β-lactamases produced by bacterial strains resistant to ceftriaxone, the full potential of ceftriaxone is restored by the addition of sulbactam. Sulbactam not only potentiates the antibacterial activity of ceftriaxone against ESBL-producing pathogens but also exhibits a moderate antibacterial activity. Disodium edetate is a non-antibiotic adjuvant acts as ARB which chelates the divalent metal ions particularly zinc that functions as a cofactor for carbapenemases. As zinc is necessary for the MBL activity, thus EDTA activity makes MBL-producing organisms susceptible toward Elores [24, 25, 42, 43]. Disodium edetate also chelates divalent metal ions located in the outer

pneumonia (HAP/CAP/VAP/HCAP).

as a treatment option for a multitude of bacterial infections.

destruction of the cell wall and ultimately in cell lysis.

**8.1. CSE1034 (Elores)**

*8.1.1. Mechanism of action*

In India, the prevalence of ESBL producing organisms among Gram-negative pathogens was up to 73.5% [26]. Similarly, the prevalence of MBLs is also increasing at an immense rate [27, 28]. Scores of reports highlighting antibiotic resistance because of efflux pump in bacteria is increasing significantly [29]. Outer membrane permeability and β-lactamase are key factor for the resistance of bacteria to antibiotics [30]. The increasing rate of the biofilm problem and its impact on antibiotic resistance triggered us to think new means which could disrupt the biofilm formation by inhibiting bacterial adhesion and curli formation.

There are significant number of reports on the clinical failure of β-lactam and β-lactamase inhibitor combination and even carbapenems due to various carbapenem resistance mechanisms. A number of studies have demonstrated the decreased susceptibility of Enterobacteriaceae to cephalosporins and other drugs [31, 32]. The ESBLs enzyme confers resistance not only to broad-spectrum cephalosporins, including oxymino-β-lactam antibiotics, but also to other commonly used antibiotics, including aminoglycosides and quinolone [33, 34]. Overexpression of efflux pump is often associated with extrusion of most of the β-lactam antibiotics, leading to decreased susceptibility of antibiotics [35].

A decreased susceptibility rates of *P. aeruginosa* and *A. baumannii* to β-lactams including carbapenems has been reported in various countries [36–38]. Failure of vancomycin and linezolid could be attributed to the emergence of VRSA (vancomycin-resistant *S. aureus*), hGISA (hetrogeneous glycopeptide intermediate *S. aureus*) [39, 40]. This has raised a huge unmet need in the search for novel resistance-breaking therapies. Besides the above factors, inappropriate selection of empiric broad-spectrum antibiotics stretches the length of treatment and causes emergence of antibiotic resistance.

In view of the above background, the increasing rate of the antibiotic resistance and its impact on treatment failure encouraged us to study newly reported concept of antibiotic adjuvant entity by which the increasing failure rate of antibiotics can be controlled. Adjuvants are commonly used chemical entities which do not possess antibacterial activity of their own but help antibiotic in breaking one or more mechanisms of resistance and accelerate antibiotic effectiveness making AAEs as empiric choice [41]. Information regarding the prevalence of antimicrobial resistance in pathogens can be used for selecting an optional treatment. Earlier studies have supported the combination therapy of two or more drugs in combination with adjuvant (which are usually non-antibiotic in nature) as a suitable approach to reduce the frequency of antibiotic resistance [24].

A few of such synergistic novel antimicrobial adjuvant entities, their mechanisms, and clinical outcomes, which can revolutionize the future, will be discussed in this book chapter. These AAEs have been developed for both Gram-positive and Gram-negative multidrug-resistant infections. Elores (ceftriaxone + sulbactam with adjuvant EDTA) and Potentox (cefepime + amikacin with adjuvant potassium chloride (KCl)) are the AAEs for Gram-negative MDR pathogens each catering to a different type of resistance, and Vancoplus (ceftriaxone + vancomycin with adjuvant L-arginine), another AAE, can help us to last longer in the war against antibiotic-resistant Gram-positive bugs particularly which cause complicated LRTI leading to pneumonia (HAP/CAP/VAP/HCAP).
