Early and Appropriate Use of Ceftazidime-Avibactam in the Management of Multidrug-Resistant Gram-Negative Bacterial Infections in the Indian Scenario

The increasing prevalence of antibiotic-resistant pathogens exerts a substantial burden on the healthcare infrastructure worldwide. The World Health Organization (WHO) has declared that multidrug-resistant (MDR) Gram-negative pathogens, especially, carbapenem-resistant Enterobacterales (CRE), Acinetobacter baumannii, and Pseudomonas aeruginosa as the topmost priority while developing newer antimicrobials. The increasing prevalence of infectious diseases caused by MDR Gram-negative bacteria also poses a challenge when choosing the empiric antimicrobial therapy for seriously ill hospitalized patients. The infections caused by MDR Gram-negative organisms ultimately result in increased mortality, morbidity, prolonged hospital stay, and increased cost of management. To tackle these challenges, newer antimicrobials like ceftazidime-avibactam were explored. The article also discusses the in vitro activity and therapeutic efficacy of ceftazidime-avibactam along with its pharmacokinetic properties and the role it will play in the management of MDR Gram-negative organisms in the Indian setting. Several studies have highlighted the role of early and appropriate antibiotic use in the reduction of mortality in patients with Gram-negative infections. Timely initiation of appropriate antibiotic therapy for serious infections leads to favorable clinical outcomes. Early and appropriate use of ceftazidime-avibactam while treating MDR Gram-negative infections has been associated with improved clinical outcomes. The aim of this review is to highlight the efficacy of ceftazidime-avibactam in the treatment of MDR Gram-negative infections. We have also summarized the information on outcomes achieved by early and appropriate use of ceftazidime-avibactam.


Introduction And Background
The emerging widespread antibiotic-resistant pathogens exert a significant burden on the healthcare infrastructure. The multidrug-resistant (MDR) Gram-negative pathogens including carbapenem-resistant Enterobacterales (CRE), Acinetobacter baumannii, and Pseudomonas aeruginosa are considered by the World Health Organization (WHO) as the highest priority while developing newer antimicrobials [1,2]. The carbapenem resistance in Enterobacterales is driven by carbapenemases such as New Delhi metallo-βlactamase (NDM), and Oxacillinase-48 like (OXA-48-like) VIM, IMP and KPC [3,4]. In India, high carbapenem resistance among Enterobacterales has been reported by the Indian Council of Medical Research (ICMR) with resistance rates up to 30% for Escherichia coli and 50% for Klebsiella pneumoniae [5]. OXA-48like gene was identified in 52% of the carbapenem-resistant (CR)-K. pneumoniae isolates while 20% isolates possessed NDM gene and 27% isolates had both NDM with OXA-48-like gene. However, in carbapenemresistant (CR)-E. coli, NDM was identified in 68% of isolates followed by OXA-48-like in 24% isolates and 8% isolates carried both NDM with OXA-48-like gene [5].
The increasing prevalence of infectious diseases caused by MDR Gram-negative bacteria places a hurdle in the selection of appropriate empiric antimicrobial therapy for seriously ill hospitalized patients [2]. The management of infections caused by CREs is more challenging owing to limited antimicrobial options. CREs exhibit resistance against conventional first-line antimicrobials including cephalosporins, β-lactam-βlactamase inhibitors, carbapenems, and fluoroquinolones [6].
Infections caused by MDR organisms are responsible for increased mortality, morbidity, prolonged hospital stay, and increased cost of management [7]. They pose a serious threat to the healthcare infrastructure owing to their difficult management. Early detection of MDR organisms can facilitate the start of appropriate antibiotic treatment and better therapeutic decisions to ensure favorable clinical outcomes and survival rates [7]. Early diagnosis can thus help in implementing improved patient management strategies and appropriate antibiotic use.
There is no concrete consensus for optimal regimens in various guidelines or experts' opinions. Colistin and tigecycline have been used as first-line therapy for managing infections caused by CREs [8]. However, tigecycline does not attain the required plasma concentrations, and hence may not be used for treating bloodstream infections [5]. Colistin has been associated with prominent toxicity (both nephrotoxicity and neurotoxicity), which may limit its clinical use [8]. Hence, these two regimens can be avoided since newer treatment modalities are available. These challenges have led to the development of newer antimicrobials such as ceftolozane-tazobactam, imipenem-cilastatin-relebactam, plazomicin, meropenem-vaborbactam, ceftazidime-avibactam, eravacycline, and cefiderocol [8].

Mechanism of action
Ceftazidime prevents bacterial cell wall synthesis which causes bacterial cell death [14]. It binds to penicillin-binding proteins (PBPs) of Gram-negative bacteria which decreases the cross-linking activity of peptidoglycan and leads to the inhibition of cell wall synthesis [15]. Avibactam is a non-β-lactam, βlactamase inhibitor which causes covalent acylation of the β-lactamase to inactivate susceptible βlactamases [9]. This structure is not hydrolyzed and is slowly separated. Avibactam is then reversed to its original structure. Avibactam does not possess antibacterial properties [16]. In vitro, avibactam exhibits activity against Ambler (a classification system for β-lactamases) class A, including TEM, SHV, CTX-M, KPC, GES, PER, SME; plasmid class C including FOX, MOX, CMY, LAT, ACC, DHA and chromosomal class C (AmpC); and class D including OXA-48 [16]. Additionally, inhibitors such as sulbactam and tazobactam are penicillin-based sulfones and lack the ability to inhibit carbapenemases [17]. Avibactam does not inhibit class B metallo-β-lactamases (NDM, VIM, IMP, VEB, PER), and OXA-23 and OXA-24/40 carbapenemases [17].

In vitro activity
In vitro activity of ceftazidime-avibactam was analyzed on isolates collected from nine centers across India between 2018 to 2019, as a part of the ATLAS (Antimicrobial Testing Leadership and Surveillance) program. The in vitro activity of ceftazidime-avibactam and comparator drugs was analyzed against E. coli (n = 458) and K. pneumoniae (n = 455) isolates. An overall susceptibility rate of over 70% was reported among K. pneumoniae and E. coli isolates. Around 51% of carbapenem-resistant (CR)-K. pneumoniae and 24% of CR-E. coli isolates were found to be susceptible to ceftazidime-avibactam [5].
The global ATLAS data collected between 2012 and 2016 reported in vitro susceptibilities of Gram-negative isolates against ceftazidime-avibactam. The study reported susceptibility of CR-E. coli to be 72.3% using Clinical Laboratory and Standards Institute (CLSI) breakpoints against ceftazidime-avibactam. Similarly, susceptibility of CR-K. pneumoniae was reported to be 85.6% using CLSI breakpoints [18].

Pharmacokinetics
The steady-state volumes of distribution of ceftazidime and avibactam were approximately 22 and 18 L. The human protein binding of both ceftazidime and avibactam is approximately 10% and 8%, respectively [9]. Around 80-90% of the injected ceftazidime is eliminated by the kidneys in its unchanged form with the renal clearance of 115 mL/min. Avibactam is excreted via the urine without alteration and has a renal clearance of 158 mL/min. In healthy adults, with normal renal function, the half-life (t1/2) of both ceftazidime and avibactam is 2.76 hours and 2.71 hours, respectively [19]. Dose adjustment is required in patients with mild, moderate, or severe renal impairment to avoid an accumulation of the drug [20]. Neither ceftazidime nor avibactam is observed to undergo significant hepatic metabolism. The potential of drug-drug interactions is low for ceftazidime-avibactam. Patients with hepatic impairment require no dose adjustments. Age, weight, gender, or ethnicity do not impact the pharmacokinetics of ceftazidime-avibactam therefore dosage adjustment is not essential [9].
Compartmental pharmacokinetic studies have shown that ceftazidime (52%), as well as, avibactam (42%) penetrate into epithelial lining fluid (ELF), which is greater than previously calculated at plasma concentrations relevant for efficacy (~ 8 mg/l for ceftazidime and ~ 1 mg/L for avibactam). These results suggest epithelial lining fluid (ELF) exposures of both drugs exceeded levels required for efficacy in plasma [21,22]. The efficacy of an antibiotic to successfully mitigate pneumonia depends on the concentration of the unbound drug available at the pulmonary infection site [22].

Real-World Evidence
The efficacy of ceftazidime-avibactam is corroborated by mounting clinical evidence. Several studies have been published in various types of primary infections including, but not limited to IAIs, UTIs, HAP, and VAP, and bacteraemia secondary to these [11,[29][30][31][32][33]. A summary of the findings has been presented in Table  2. The real-world evidence is indicative of favorable efficacy results which were consistent even in MDR infections.

Early and appropriate use of ceftazidime-avibactam
Early detection of MDR organisms helps in deciding the appropriate antibiotic for the treatment of infections. Thus, facilitating better therapeutic decisions to ensure favorable clinical outcomes and survival rates. Conventional specimen culture is one such diagnosis method that is used to identify causative organisms in about 48 hours [7]. The causative organisms after isolation can be subjected to molecular testing (also known as genotyping) or phenotypic testing of bacterial antimicrobial susceptibility at the discretion of the treating physician.
Phenotypic testing includes diffusion method, dilution method, E-test, broth macro and micro dilution, and Matrix-Assisted Laser Desorption Ionization-Time of Flight Mass Spectroscopy (MALDI-ToF) [43]. Molecular testing includes polymerase chain reaction (PCR), DNA microarray and DNA chips, and loop-mediated isothermal amplification (LAMP). The newer molecular diagnostic methods generate results within one to four hours. This enables physicians to optimize a targeted treatment for the patients in a timely manner. Overall, this may lead to a decrease in mortality, shorter hospital stays, and a reduction in hospitalization costs [44][45][46][47]. Rapid diagnostics is associated with early intervention with effective antimicrobial therapy which may lead to improved clinical outcomes and decreased mortality [48].
Multiplex real-time PCR technique assay can be utilized for rapid detection of carbapenemase genes in the infection-causing isolates. It can detect five carbapenemase genes (KPC, NDM, VIM, IMP-1, and OXA- 48) and has good concordance rates of between 90 to 100% [49]. The evolution of rapid diagnostics has reduced the time required to get the results. This has led to positive effects on clinical outcomes in patients and also has contributed to the efforts to counter antimicrobial resistance in conjunction with robust antimicrobial stewardship programs [50]. A rapid turn-around time to obtain test results leads to a shorter time to initiate optimal therapy. The subsequent advantages of using rapid diagnostic tools and antimicrobial stewardship programs include a decrease in mortality rates, shorter hospital lengths of stay, and reduced hospital costs [50]. Early diagnosis of MDR organisms can thus help in implementing improved management strategies and standardizing antimicrobial stewardship policies. The information on the turn-around time of various diagnostic tests is presented in Table 3 [44][45][46][47].  Inappropriate use of broad-spectrum antimicrobials is responsible for increased antimicrobial resistance (AMR). It is also responsible for an increase in the rate of adverse events in up to 20% of patients [51]. The American College of Physicians (ACP) and the Centers for Disease Control and Prevention (CDC) have reported an estimate of over 2.6 million diseases and 35900 deaths annually due to AMR. They also have reported the incidence of resistant infections to be 6.1/10000 person-days after receiving antibiotics [51]. A multivariable survival analysis conducted on 789 patients suffering from E. coli, Klebsiella spp. and P. aeruginosa caused bacteremia, demonstrated that the patients who received an effective antibiotic early (hazard ratio {HR} -1.26, confidence interval i.e., CI -0.78 to 2.06) had better survival rate as compared to those who did not (HR -1.83, CI -1.05 to 3.20) [52]. In patients suffering from infections caused by resistant Gram-negative organisms, delayed appropriate therapy rates remain high. As a consequence, the negative impact of increased duration of therapy (+4.5 days) and delayed recovery (+4.9 days) have been observed [53]. A retrospective analysis concluded that delayed appropriate therapy is an independent factor related to unfavorable clinical outcomes as compared to timely appropriate therapy among hospitalized patients with serious infections due to Gram-negative bacteria, regardless of resistance status. The patients who received delayed appropriate therapy experienced an approximate 70% increase in length of stay, about 65% increase in total in-hospital costs and approximately 20% increase in the risk of in-hospital mortality or discharge to hospice [53]. Early and appropriate antibiotic use results in the reduction in mortality in patients with sepsis [54,55].
Several clinical studies have highlighted the importance of timely initiating antibiotic therapy for serious infections to obtain favorable clinical outcomes. The summary has been presented in

Guideline recommendation of usage of ceftazidime-avibactam
Infectious Diseases Society of America (IDSA) has recommended ceftazidime-avibactam as a first-line treatment against OXA-48-like and KPC-producing carbapenem-resistant Enterobacterales for pyelonephritis or cUTI and infections outside of the urinary tract, in cases with proven in vitro susceptibility to ceftazidime-avibactam [60]. The Indian Council of Medical Research (ICMR) has recommended that ceftazidime-avibactam be used as a first-line treatment option against OXA-48-like carbapenem-resistant Enterobacterales [61].

Role of ceftazidime-avibactam in the Indian setting
In India, NDM and coproduction of NDM with OXA-48-like enzymes are the most prevalent mechanisms of CRE infections [62]. Ceftazidime-avibactam has been established to be effective in patients with comorbid conditions. The real-world evidence and clinical experience published consisted of patients with comorbidities such as obesity, impaired renal function, diabetes, heart failure, liver diseases, malignancies [11], asthma, chronic pancreatitis [33], neurological diseases, bronchiectasis, etc. [31] among others. Sub-group analyses of REPROVE (ceftazidime-avibactam versus meropenem in nosocomial pneumonia, including ventilator-associated pneumonia) and RECLAIM (Efficacy and Safety of Ceftazidime-Avibactam Plus Metronidazole Versus Meropenem in the Treatment of Complicated Intra-abdominal Infection) studies were performed on data of Indian patients [26,28]. Both the analyses concluded that ceftazidime-avibactam was an effective alternative to meropenem in HAP and complicated IAIs (cIAIs) in Indian patients. The results of both the studies were in-line with the results of the overall results and the safety profile was consistent with the adverse effects previously reported for ceftazidime and cephalosporins [26,28]. The real-world studies from India have reported high susceptibility of tested CRE isolates to ceftazidime-avibactam [29] and also concluded that ceftazidime-avibactam is a viable option to treat patients with CRE infections [30].
A rise in carbapenem-resistant Gram-negative organisms has been observed worldwide. Carbapenemresistant P. aeruginosa, Acinetobacter baumannii and CREs remain the major cause of hospital-acquired infections. This will inevitably lead to complicated treatment scenarios and more serious infections in vulnerable patient populations [63]. The current treatment options against MDR Gram-negative bacteria include polymyxins, aminoglycosides, tigecycline, carbapenems, fosfomycin, and newer β-lactam-βlactamase inhibitors [64].
Tigecycline and colistin face challenges such as low plasma concentration and nephrotoxicity, respectively [5,65,66]. Colistin may be limited in its use due to its narrow therapeutic index, challenges with dose optimization, poor lung penetration, nephrotoxicity, and emerging antimicrobial resistance [61,65,67]. Antimicrobial resistance against colistin is emerging due to its rampant use. The susceptible category was removed from colistin by the CLSI indicating that some causative organisms might not respond to it owing to the unknown resistance mechanism [61]. Tigecycline has an expanded broad-spectrum activity which overcomes the resistance issues of tetracycline [68]. However, tigecycline has been reported to fail in achieving the required time curve and minimum inhibitory concentration ratio leading to treatment failure [69]. Tigecycline additionally faces challenges with regard to susceptibility testing due to inconsistency in results obtained from various antimicrobial susceptibility tests [70].
Ceftazidime-avibactam has been proven to be efficacious and, in some studies, non-inferior to conventional options in treating complicated infections [13,25,27]. There is limited literature available highlighting the importance of early use of antibiotics for treating infections caused by multidrug-resistant bacteria. However, clinical studies have stressed the association between delayed appropriate therapy and the risk of prolonged symptoms and treatment duration [53]. Prolonged hospital stays and treatment duration results in an increased economic burden for the patients and the healthcare infrastructures. It is hence crucial to alter the treatment practices from escalation strategies and adopt early and appropriate antibiotic therapy in patients with serious infections caused by Gram-negative bacteria [53].

Conclusions
The increasing prevalence of antimicrobial resistance and infections caused by MDR Gram-negative bacteria jeopardize the current management strategies. Treating infections caused by CREs is more challenging owing to limited antimicrobial options. Ceftazidime-avibactam, a combination of the third-generation cephalosporin and a non-β-lactam-β-lactamase inhibitor, has been proven to be clinically efficacious in pivotal phase III non-inferiority trials as well as in real world settings. A decreased mortality rate was observed with early and appropriate use of ceftazidime-avibactam for managing infections caused by pathogens which are sensitive to ceftazidime-avibactam.
Furthermore, the use of rapid diagnostic tools can support prompt administration of effective therapy and help in reducing the morbidity and mortality associated with MDR infections. Ceftazidime-avibactam fits the role of an effective antibiotic with a favorable safety and pharmacokinetic profile. The early and appropriate use of ceftazidime-avibactam yields improved clinical outcomes for the patients whose profiles are suitable to receive early treatment. Further real-world evidence studies focusing on time of ceftazidimeavibactam treatment initiation are needed to ascertain the advantages of its early and appropriate use on a larger scale.

Conflicts of interest:
In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: Abhisek Routray and Akshata Mane declare(s) employment from Pfizer Ltd. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.