Antimicrobial resistance is one of the major issues faced globally posing a serious threat to the effective prevention and treatment of an ever-increasing range of resistant bacterial infections.1 The rapid pace of multi-drug-resistance (MDR) if left unattended can very soon land us in an era where common infections and minor injuries can become difficult to treat and end up as one of the prime causes of mortality. Although resistance trends vary among populations, there is significant evidence that the prevalence of MDR is increasing.2 According to WHO global report on surveillance, resistance in common bacterial pathogens has reached to alarming levels in many parts of the world and very few treatment options are effective against common infections in these regions.2 Infections due to MDR organisms can result in increased treatment costs, longer lengths of hospital stay and higher mortality rates.1,3

In recent years, a growing resistance among Gram-positive and Gram-negative pathogens causing community or hospital-based infections is on rise.4 The acronym “ESKAPE” has been coined for a faction of antibiotic-resistant pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumanii, Pseudomonas aeruginosa, and Enterobacter species) capable of escaping the biocidal effects of antimicrobial agents and are currently posing serious therapeutic dilemmas to medical practitioners.1 The mechanism of resistance among these infectious agents mainly include production of extended-spectrum beta-lactamases (ESBLs) and carbapenameses in Gram-negative pathogens, and due to mutant transpeptidase gene in Gram-positive organisms that have low affinity for beta-lactams.5,6 The production of these enzymes renders the current range of antibiotics which mainly include beta-lactamase inhibitors ineffective against these resistant pathogens. The biggest concern is that the drug of last resort for these infections is also reported to be repeatedly failing due to rise in development of resistance of the causative pathogens to these drugs and can very soon leave us with no choice of antibiotics for these MDR infections.5,6 Thus, all these studies argue for an augmentation of research on drug resistance and identify or develop new therapeutic strategies to widen the treatment horizon for effective infection control and antimicrobial use.

Elores, a novel Antibiotic Adjuvant Entity (AAE) of Ceftriaxone, Sulbactam and EDTA, herein referred as CSE-1034, has been recently developed and proposed as alternative option to solve the MDR menace to some extent. Due to synergistic action of inhibition of cell wall by ceftriaxone accompanied by the specific inhibition of beta-lactamases by beta-lactamase inhibitor component sulbactam and the non-antibiotic adjuvant EDTA acting as a catalyst and providing synergy to the combination. This drug has been reported to be effective against multiple type of MDR organisms.7,8 Clinical trials of CSE-1034 revealed that many MDR organisms resistant to other antibiotics, were sensitive to this novel AAE, which can serve as a potential alternative therapy to reduce the usage of currently available drugs like Pip tazo and carbapenems for these bacterial infections.9 This drug got approval from Indian FDA after phase III clinical trials and was there after marketed in India for the treatment of various bacterial infections. In order to check the efficacy and safety of this drug in real-world practice, a post marketing surveillance study was conducted immediately after CSE-1034 was launched in the market. In this article, we present the results of this post-marketing surveillance of CSE-1034 used in everyday clinical practice in a decent number of patients.

The clinical trials for drugs are usually conducted in controlled environment with a number of limiting factors including the number of patients enrolled, age, associated co-morbidities, and medical history. Thus, the information retrieved through clinical trials is not the right way to predict drug effectiveness and safety in the real-world settings. Therefore, it becomes very important to collect and evaluate the drug further after being launched in the market. One of the recent drugs that was launched in market in 2011 as a potential treatment option for various bacterial infections was CSE-1034. This PMS study was undertaken to evaluate the safety and efficacy of CSE-1034 for the treatment of various MDR bacterial infections in IPD population under routine clinical settings.

Most of the patients evaluated in this study were adults aged 18–65 (60%) followed by pediatric (30%) and geriatric (10%) patients. LRTI was observed to be the most common (52%) infection followed by UTI (23.9%), enteric fever (7.4%), surgical infections (7.12%), bacterial sepsis (5.4%), bacterial meningitis (2.2%), bone and joints infection (1.4%), and skin and soft tissue infections (0.56%), well in accordance with various previous studies that have demonstrated a similar kind of infection pattern.10 The most frequent cause of these bacterial infections was E. coli (17%) followed by A. baumannii (12%), S. pneumoniae (12%), P. aeruginosa (8%), S. typhii (7%), and K. pneumoniae (6%). Overall, the Gram-negative pathogens were predominant as compared to Gram-positive pathogens.

Evaluating the drug in terms of safety, 409 AEs were reported in 211 patients accounting to 8.4% incidence. The common AEs reported were vomiting (3.0%), pain at injection site (2.5%), nausea (2.3%), redness at site (1.96%), thrombophlebitis (1.4%), and fever (1.0%). All reported AEs are known to be commonly associated with the antibiotic treatment of these bacterial infections. The most common systems affected by AEs were skin manifestations and general disorders followed by GI, vascular, and nervous system disorders. Consistent with our observations, a multitude of previous reports described a similar kind of pattern of organ/systems associated with AEs with various anti-bacterial drugs.11,12

When compared to the incidence of ADRs associated with other drugs of choice for multi-drug resistant infections, the incidence of ADRs was lower for this novel antibiotic Adjuvant Entity. In a meta-analysis study on the adverse effects of doripenem and other comparative drugs for the treatment of various bacterial infections 21–23% of the patients reported AEs for all the drugs compared.13 Similarly, a multi-center study evaluating and comparing the efficacy of meropenem to cefuroxime-gentamicin (±metronidazole) for the treatment of serious bacterial infections in elderly patients reported treatment-related AEs in 48.7% in meropenem-treated patients and in 45% with combination therapy14 (12). Likewise, in another similar kind of safety analysis study, treatment-related AEs were reported in 64% of patients receiving dorepenem and 60% of the patients receiving levofloxacin for the treatment of UTI.15 Furthermore, these studies have also reported that around 5–10% serious AEs were associated with the treatment.13,15 In contrast, no treatment-related ADRs belonging to grade IV or V was reported in any of the patients in our study. Furthermore, it should be emphasized that age-wise comparison of AEs has shown that the lowest number of AEs were reported in pediatric patients, thus it can also be concluded that this drug can be safely used in children as well. ADRs are one the main causes of healthcare-associated morbidity and mortality.16 In US, an estimated 7000 deaths occur due to ADRs making it the fourth leading cause of death in US.17 Not only do ADRs cause death and injury but they also affect the length of stay in hospitals which in turn lead to increased healthcare costs and decreased patient productivity.18 Thus overall, low incidence of AEs associated with this drug particularly in pediatric patients makes it an ideal alternative in terms of lower mortality rate and lower financial burdens associated with it.

Evaluating the risk factors for AEs, three factors including age, sex, and associated co-morbidities were observed to be significantly related to the occurrence of ADRs. Overall AEs reported in this study were more common in the geriatric group compared to the pediatric and adult groups. This kind of drug behavior could possibly be associated with decreased drug tolerance, reduced capacity to metabolize19 and eliminate drugs,20 and multiple medical problems associated with the growing age. Supporting our data, a study by Debellis et al.21 has shown that the incidences of ADRs are common and often preventable among older persons in the ambulatory clinical settings. Similarly, various other studies have shown that older people are more than twice as susceptible to ADRs as younger people.22,23 The increased rate of AEs among females could possibly be attributed to anatomical and physiological differences including body weight, body fat, gastrointestinal factors, menopause, menstruation, etc. which could affect pharmacokinetics and pharmacodynamics of drugs in the body.24,25 A group of studies have reported pronounced differences in the incidences of ADRs between two genders.16,26 The rate of AEs were also reported to be higher in patients with associated co-morbidities indicating that concomitant disease may also influence susceptibility to ADRs. In agreement with our results, various studies have shown that co-morbidities can form a very important factor leading to drug–disease interaction and ADRs.27,28 Commonly associated co-morbidities that have been widely shown to increase treatment-related AEs due to enhanced drug–disease interactions include diabetes, irregular blood pressure, insomnia, ulcer, glaucoma, enlarged prostate, and poor bladder control.27,28

This PMS study also demonstrated that CSE-1034 is an effective treatment in IPD patients with various MDR bacterial infections with cure rates in 79.62% of the patients and clinical improvement seen in 20.17% of the patients. In the subgroup analysis based on age, pediatric patients had the highest clinical response rate with 84% reporting total cure and 16% reporting clinical improvement; the cure rate of adults was 78% and clinical improvement 21%. Geriatric patients had a 72% cure rate and 27% clinical improvement. Infections caused by E. coli had the highest cure rate of 91% followed by 79% of infections by K. pneumoniae, 79% by A. baumannii, and 73% by S. pneumoniae. The results of clinical cur rate were in accordance with microbial susceptibility. The clinical response rates of CSE-1034 observed in this study are consistent with the results of prior studies conducted with this novel antibiotic to evaluate its effectiveness.7,29 Currently, the widely used class of drugs to treat adult and pediatric patients with serious MDR infections includes the penem family. When compared to the comparator drugs, the clinical cure rate with this drug is at par or in some cases better than the best available drugs of choice in the market for MDR infections.13,30

Thus, these results overall suggests that CSE-1034 is a valuable alternative to penems because of several advantages like the low rate of ADRs events. Secondly, no serious grade III or IV AE was associated with it. Thirdly, the clinical effectiveness of this drug was comparable to other drugs because patients who did not respond to Pip tazo and Cefoperazone sulbactam responded well on CSE1034. Therefore, CSE1034 can help us to minimize the usage of penems and spare them for the situations where they are actually demanded.

The CSE-1034 was well-tolerated and effective for IPD patients of all age groups having different MDR bacterial infections. The low rate of ADRs associated with the drug along with the high clinical effectiveness make it an ideal alternative for the treatment of various bacterial infections.

The authors declare no conflicts of interest.