**8.1. CSE1034 (Elores)**

**8. Antibiotic resistance**

128 Contemporary Topics of Pneumonia

gation, and curli fiber formation [17, 20–25].

by inhibiting bacterial adhesion and curli formation.

emergence of antibiotic resistance.

frequency of antibiotic resistance [24].

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 conju-

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

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

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

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

β-lactam antibiotics, leading to decreased susceptibility of antibiotics [35].

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 as a treatment option for a multitude of bacterial infections.

#### *8.1.1. Mechanism of action*

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 destruction of the cell wall and ultimately in cell lysis.

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 membrane causing destabilization of outer membrane and thus resulting in enhanced penetration of drugs inside the bacterial cells. Moreover, CSE1034 downregulates acrA, acrB, tolC, mexA, and mexB genes in MexA-MexB-OprM efflux pump, which in turn enhances the susceptibility of Gram-negative bacteria (GNB) toward CSE1034 which overexpress this efflux transporter.

*8.2.1. Mechanism of action*

Amikacin, which belongs to aminoglycoside antibiotic group, blocks the production of protein by binding irreversibly to the four nucleotides of 16S rRNA of 30S ribosomal subunit of the pathogenic organism. This region where amikacin binds is known to interact with the wobble base in the anti-codon of tRNA. Thus, amikacin interferes with the tRNA acceptor site and prevents the formation of initiation complex with messenger RNA. This leads to misreading of mRNA so incorrect amino acids are inserted into the polypeptide leading to nonfunctional or toxic peptides and the breakup of polysomes into nonfunctional monosomes.

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

http://dx.doi.org/10.5772/intechopen.69979

131

Cefepime, a fourth-generation cephalosporin, is bactericidal and has the same mode of action as other β-lactam antibiotics. It disrupts the synthesis of the peptidoglycan layer of bacterial

Potassium chloride is a metal halide salt composed of potassium and chloride that is used as an adjuvant in Potentox. Interestingly, Potentox due to adjuvant potassium chloride exhibits activity against Quinolone-resistant Gram-negative pathogens, the prevalence of which is ris-

Both cefepime and amikacin individually have become a victim of high level of resistance [52]. This is where precisely, Potentox is used in combating these multidrug-resistant pathogens as Potentox has demonstrated in vitro and in vivo activity against these resistant isolates to which cefepime and amikacin are resistant individually. Global surveillance studies demonstrate that the actual acquired fluoroquinolone resistance rates are highly variable and are as high as almost 100%, particularly in Asia, whereas resistance rates in Europe and North America range from <10% in rural areas to >30% which is still pretty high. This highlights the importance of Potentox use to target multiple drug resistance effectively which developed

Multi-centric randomized comparative open-labeled phase 3 trial of synergistic antibiotic combination of cefepime and amikacin versus cefepime alone was conducted in nosocomial

Potentox and Elores can serve as a true carbapenem sparer as medically important Gramnegative bacteria are developing resistance very fast against this valuable class of antibiotic. In the era of antimicrobial resistance, the judicious use of different antimicrobials in a bal-

While we look for HAP/VAP due to Gram-positive bacteria, methicillin-resistant *S. aureus* is a big concern and empirical antibiotic therapy should cover MRSA whenever factors increase the likelihood of MRSA. Now, MRSA is not confined to western countries only. A network of microbiology laboratories (Indian Network for Surveillance of Antimicrobial Resistance—INSAR) at premier medical colleges and hospitals in India was formed with support from the World Health Organization. In an article published in 2013, INSAR reported that MRSA prevalence in India is to the tune of 40% which shows that MRSA is a significant problem for India too.

pneumonia and showed superiority of Potentox in efficacy over cefepime alone.

anced fashion can help us in preserving these antibiotics for longer duration.

cell wall which is important for cell wall structural integrity.

ing alarmingly in developing countries.

both in community and in hospital settings.

*8.2.2. Activity spectrum*

**8.3. Vancoplus**

#### *8.1.2. Activity spectrum*

Elores has a broad spectrum of activity against both Gram-positive and Gram-negative bacteria pathogens. It is reported to be active against both ESBL and MBL producing organisms, including *E. coli, K. pneumoniae, Acinetobacter* spp., and *Pseudomonas* spp. Susceptibility data from various parts of India were collected from various clinical samples (including urine, pus, sputum, bronchoalveolar lavage, and endotracheal fluid); this AAE is very promising. The prevalence of resistance to Elores in ESBL and MBL organisms is reported to be less in various parts of India. The drug has been approved by the Drug Controller General of India (DCGI) for the treatment of various bacterial infections caused by the susceptible isolates of *K. pneumoniae, K. oxytoca, E. coli, P. aeruginosa, Acinetobacter* spp., *S. pneumoniae*, and *S. aureus*. A number of randomized phase 3 comparative trials, prospective, retrospective, and case studies have demonstrated the efficacy of Elores in the treatment of infections pertaining to respiratory tract, skin and skin structure, genitourinary tract, musculoskeletal, and gastrointestinal tract when compared with carbapenems and BL-BLIs showed very promising results [24, 25, 42]. These various published susceptibility reports suggest the use of Elores empirically in HAP and VAP caused due to MDR ESBL and MBL-producing Gram-negative pathogens [44]. A number of studies including randomized phase 3 trials, prospective, retrospective, and case studies validate the safety and efficacy of CSE1034. A phase 3 trial reports published in 2013 showed significantly high improved efficacy of CSE1034 compared to ceftriaxone in LRTI patients [45, 46]. Based on the safety and efficacy data, Elores is recommended as a carbapenem-sparer antibiotic. CSE1034 has shown to be effective and safe in moderate to severe HAP and VAP patients. CSE1034 has shown promising results in sepsis as monotherapy as well as along with colistin [47, 48]. CSE1034 was found to be safe with no serious adverse event was reported in phase 3 trial and postmarketing surveillance studies. Overall, CSE1034 is found to be well tolerated in adult population.

#### **8.2. Potentox**

With regard to Potentox for pneumonia, first of all, let's see what this unique AAE offers. Potentox is a synergistic antibiotic combination of cefepime and amikacin and potassium chloride. Cefepime is the fourth-generation broad-spectrum cephalosporin. It is frequently used as first-line empirical therapy for healthcare-associated infections, including those caused by suspected Gram-negative bacteria. Cefepime has relatively low propensity for degradation by ESBLs compared to other cephalosporins. Cefepime also remains active against infections due to AmpC-producing organisms. Amikacin is one of the most commonly used aminoglycosides and it has the highest recommendation from IDSA 2016 for usage in nosocomial pneumonia cases as an empirical antibiotic in the combination protocol against nosocomial pneumonia. Potentox (cefepime + amikacin) is not just the most active combination in vitro [23, 49] but also has demonstrated efficacy in vivo as the most active combination [50, 51].

#### *8.2.1. Mechanism of action*

membrane causing destabilization of outer membrane and thus resulting in enhanced penetration of drugs inside the bacterial cells. Moreover, CSE1034 downregulates acrA, acrB, tolC, mexA, and mexB genes in MexA-MexB-OprM efflux pump, which in turn enhances the susceptibility of Gram-negative bacteria (GNB) toward CSE1034 which overexpress this

Elores has a broad spectrum of activity against both Gram-positive and Gram-negative bacteria pathogens. It is reported to be active against both ESBL and MBL producing organisms, including *E. coli, K. pneumoniae, Acinetobacter* spp., and *Pseudomonas* spp. Susceptibility data from various parts of India were collected from various clinical samples (including urine, pus, sputum, bronchoalveolar lavage, and endotracheal fluid); this AAE is very promising. The prevalence of resistance to Elores in ESBL and MBL organisms is reported to be less in various parts of India. The drug has been approved by the Drug Controller General of India (DCGI) for the treatment of various bacterial infections caused by the susceptible isolates of *K. pneumoniae, K. oxytoca, E. coli, P. aeruginosa, Acinetobacter* spp., *S. pneumoniae*, and *S. aureus*. A number of randomized phase 3 comparative trials, prospective, retrospective, and case studies have demonstrated the efficacy of Elores in the treatment of infections pertaining to respiratory tract, skin and skin structure, genitourinary tract, musculoskeletal, and gastrointestinal tract when compared with carbapenems and BL-BLIs showed very promising results [24, 25, 42]. These various published susceptibility reports suggest the use of Elores empirically in HAP and VAP caused due to MDR ESBL and MBL-producing Gram-negative pathogens [44]. A number of studies including randomized phase 3 trials, prospective, retrospective, and case studies validate the safety and efficacy of CSE1034. A phase 3 trial reports published in 2013 showed significantly high improved efficacy of CSE1034 compared to ceftriaxone in LRTI patients [45, 46]. Based on the safety and efficacy data, Elores is recommended as a carbapenem-sparer antibiotic. CSE1034 has shown to be effective and safe in moderate to severe HAP and VAP patients. CSE1034 has shown promising results in sepsis as monotherapy as well as along with colistin [47, 48]. CSE1034 was found to be safe with no serious adverse event was reported in phase 3 trial and postmarketing surveillance studies. Overall, CSE1034 is found to be well tolerated in adult

With regard to Potentox for pneumonia, first of all, let's see what this unique AAE offers. Potentox is a synergistic antibiotic combination of cefepime and amikacin and potassium chloride. Cefepime is the fourth-generation broad-spectrum cephalosporin. It is frequently used as first-line empirical therapy for healthcare-associated infections, including those caused by suspected Gram-negative bacteria. Cefepime has relatively low propensity for degradation by ESBLs compared to other cephalosporins. Cefepime also remains active against infections due to AmpC-producing organisms. Amikacin is one of the most commonly used aminoglycosides and it has the highest recommendation from IDSA 2016 for usage in nosocomial pneumonia cases as an empirical antibiotic in the combination protocol against nosocomial pneumonia. Potentox (cefepime + amikacin) is not just the most active combination in vitro [23, 49] but also has demonstrated efficacy in vivo as the most active combination [50, 51].

efflux transporter.

population.

**8.2. Potentox**

*8.1.2. Activity spectrum*

130 Contemporary Topics of Pneumonia

Amikacin, which belongs to aminoglycoside antibiotic group, blocks the production of protein by binding irreversibly to the four nucleotides of 16S rRNA of 30S ribosomal subunit of the pathogenic organism. This region where amikacin binds is known to interact with the wobble base in the anti-codon of tRNA. Thus, amikacin interferes with the tRNA acceptor site and prevents the formation of initiation complex with messenger RNA. This leads to misreading of mRNA so incorrect amino acids are inserted into the polypeptide leading to nonfunctional or toxic peptides and the breakup of polysomes into nonfunctional monosomes.

Cefepime, a fourth-generation cephalosporin, is bactericidal and has the same mode of action as other β-lactam antibiotics. It disrupts the synthesis of the peptidoglycan layer of bacterial cell wall which is important for cell wall structural integrity.

Potassium chloride is a metal halide salt composed of potassium and chloride that is used as an adjuvant in Potentox. Interestingly, Potentox due to adjuvant potassium chloride exhibits activity against Quinolone-resistant Gram-negative pathogens, the prevalence of which is rising alarmingly in developing countries.
