|Year : 2017 | Volume
| Issue : 4 | Page : 685-690
Antibiotic/adjuvant combinations (ceftriaxone + sulbactam + adjuvant disodium edetate) as an alternative empiric therapy for the treatment of nosocomial infections: Results of a retrospective study
Saibal Chakravorty, Prashant Arun
Department of Internal Medicine, Intensive Care Unit, Metro Hospital, Noida, Uttar Pradesh, India
|Date of Web Publication||30-Jul-2018|
Dr. Saibal Chakravorty
Department of Internal Medicine, Intensive Care Unit, Metro Hospital, Noida, Uttar Pradesh
Source of Support: None, Conflict of Interest: None
OBJECTIVE: Carbapenems are one of the last therapeutic options to treat various bacterial infections including multidrug resistant (MDR) nosocomial infections. However, excessive and inappropriate prescription of this drug has recently led to an epidemic rise in carbapenem resistance. Optimizing antibiotic utilization and exploring alternate options can be a potential way to control carbapenem resistance. The aim of this study was to assess the clinical efficacy of novel antibiotic adjuvant entity (ceftriaxone + sulbactam + ethylenediaminetetraacetic acid [EDTA] [CSE-1034]) in the treatment of various nosocomial infections. METHODS: Older patients suffering from hospital-acquired pneumonia, ventilator-associated pneumonia, and complicated urinary tract infections who received CSE-1034 as empirical therapy were evaluated. CSE-1034 therapy was initiated empirically and continued based on the results of culture sensitivity and clinical outcome. RESULTS: In total, 59 culture-positive patients with mean age of 57 ± 19 years were evaluated in this retrospective study. Escherichia coli was the most predominant pathogen isolated, followed by Acinetobacter baumannii, Klebsiella pneumonia, and Pseudomonas aeruginosa. Microbial sensitivity analysis has shown that isolates from all patients exhibited resistance to multiple classes of antibiotics. Isolated pathogens from 78% were sensitive to meropenem, 86% to CSE-1034, and 100% to colistin except Proteus species. Overall assessment of clinical outcome has shown that 83% cases were cured with CSE-1034 monotherapy, 12% with CSE-1034 and colistin combination therapy, and 5% were cured with alternate meropenem therapy. CONCLUSION: From this study, it can be concluded that ceftriaxone + sulbactam + EDTA alone or in combination with colistin can be an effective empiric treatment of various MDR nosocomial infections and can serve as an effective alternative to carbapenems.
Keywords: Colistin, complicated urinary tract infection, CSE-1034, hospital-acquired pneumonia, multidrug resistance, ventilator-associated pneumonia
|How to cite this article:|
Chakravorty S, Arun P. Antibiotic/adjuvant combinations (ceftriaxone + sulbactam + adjuvant disodium edetate) as an alternative empiric therapy for the treatment of nosocomial infections: Results of a retrospective study. Indian J Cancer 2017;54:685-90
|How to cite this URL:|
Chakravorty S, Arun P. Antibiotic/adjuvant combinations (ceftriaxone + sulbactam + adjuvant disodium edetate) as an alternative empiric therapy for the treatment of nosocomial infections: Results of a retrospective study. Indian J Cancer [serial online] 2017 [cited 2019 Aug 22];54:685-90. Available from: http://www.indianjcancer.com/text.asp?2017/54/4/685/237892
| » Introduction|| |
Nosocomial infections are the opportunistic infections acquired by patients after getting admitted to hospital and is a big threat faced by hospitalized patients, particularly in Indian subcontinent where the rate is almost double when compared with the West. Various factors that facilitate transmission and growth of these opportunistic microorganisms in patients include a weaker immune system, hospital environment, and, most importantly, examinations and treatments that include invasive procedures. The most frequent and serious nosocomial infections include urinary tract and respiratory tract infections.
Hospital-associated infections are mainly caused by Gram-negative bacteria in Indian subcontinent, and the growing antibiotic resistance among these bacterial strains poses a big challenge in treating these infections. Hospitalized patients with multidrug resistant (MDR) infections appear to have increased mortality and morbidity rates, increased cost of healthcare because of added antimicrobial treatment, and prolonged hospitalization, The negative clinical and economic impact of these MDR pathogens warrants in-depth evaluation of strategies to prevent nosocomial infections. Earlier, beta-lactam antibiotics were the drug of choice for the treatment of various bacterial infections. Nevertheless, the emergence of extended-spectrum β-lactamases (ESBL) strains limited cephalosporin utility and carbapenems were introduced in clinical settings. Although carbapenems have demonstrated adequate effectiveness for the treatment of bacterial infections caused by ESBL-producing pathogens, carbapenem resistance has been reported worldwide., The indiscriminate use of carbapenems has led to an alarming increase in metallo-beta-lactamase (MBL) producing isolates which if left unchecked can leave us with no antibiotic choices. Various studies have suggested that antibiotic adjuvant therapies can be an alternate approach to curb the rate of drug resistance in microorganisms. A new antibiotic adjuvant entity of ceftriaxone + sulbactam + adjuvant disodium edentate, which has been reported to have proven efficacy in a wide range of infections,, was thus considered for evaluation in patients suffering from various nosocomial infections.
| » Materials and Methods|| |
The patients included in this retrospective study were patients suffering from hospital-acquired pneumonia (HAP), ventilator-associated pneumonia (VAP), and nosocomial complicated urinary tract infection (cUTI) and presenting for treatment between January 2016 and December 2016. The study was conducted as per the current norms for observational studies and as per the ethical principles of Declaration of Helsinki. As the study was retrospective in nature, informed consent was not required.
In all, 59 patients who were 18 years and older who fulfilled inclusion criteria were only included in the study. The main inclusion criteria were (a) primary diagnosis of HAP, VAP, and cUTI based on relevant signs and symptoms and various laboratory parameters; (b) received CSE-1034 as empirical treatment; and (c) hospitalized for >5 days. Patients who died within 72 h because of multiple complications other than antibiotic failure were excluded from the analysis.
Symptoms of HAP included clinical features such as fever (>38°C), leukocytosis (>12,000 white blood cell [WBC]/mL), purulent endotracheal (ET) secretions, radiological features, and culture sputum positive for microorganisms. Other symptoms include new onset of worsening cough, dyspnea, tachycardia, rales, or bronchial breath sounds.
VAP was identified in mechanically ventilated patients by the presence of various symptoms including fever (>100.4 F), leukocytosis (>12,000 WBC/mL), chills, rigor, chest pain, cough and dyspnea, increased respiratory rate or heart rate, or changes in respiratory parameters such as increase in purulent secretions/sputum or worsening hypoxemia, abnormal chest radiographs, and semi-quantitative culture of ET positive for pathogen.
Nosocomial UTI was identified in patients with indwelling urethral, indwelling suprapubic, or intermittent catheterization and without other identifiable source in patients, and the symptoms included fever without any localized findings, suprapubic or costovertebral angle tenderness, and otherwise unexplained systemic symptoms such as altered mental status, hypotension, or evidence of a systemic inflammatory response syndrome or recent trauma.
Data collection and analysis
The patients were identified through the department's patient file archive. All relevant information regarding demographic and baseline characteristics such as gender, age, infection type, source of infection, causative pathogen, dosage, and regimen of antibiotic therapy were recorded and analyzed.
CSE-1034 was initially started empirically in all the selected patients based on clinical presentation and the decision of the treating physician and was further continued or shifted based on in vitro microbiological susceptibility report and clinical response.
The clinical response of the therapy was evaluated in terms of improvement in infection-related signs and symptoms after 3 days of treatment initiation and at the end of the treatment.
Patients in all groups were eligible to switch over to other treatment regimens after 3 days of empirical therapy depending on the microbial sensitivity data and clinical response.
A dose of 3.0 g/12 h of CSE-1034, 1.0 g/8 h of meropenem, and colistin with a loading dose of 9 MIU followed by BD doses of 4.5 MIU was used. Standard dose adjustment as per requirement was done for colistin.
In vitro microbial antibiotic susceptibility testing
Kirby–Bauer disk diffusion method/Vitek automated system was used to test antimicrobial susceptibility of the pathogen isolated from the patients, and the results were interpreted as per the interpretation criteria of the Clinical and Laboratory Standards Institute standards. Using breakpoints provided by the manufacturer, antimicrobial susceptibility for CSE-1034 was performed. Sensitivity Criteria for Enterobacteriaceae were >23mm - S, 20–22-I, and ≤19-R and for Gram-negative bacilli were >21 mm - S, 14–20-I, and ≤13-R.
Based on antimicrobial sensitivity, the patients were divided into two groups. About 51 patients showing sensitivity toward CSE-1034 were included in Group 1, whereas 8 patients who were resistant to CSE-1034 were included in Group 2. Patients in Group 1 were further divided into subgroups depending on the response to CSE-1034 treatment on the third day. Group 1A consists of 49 patients who showed improvement in clinical signs and symptoms with CSE-1034 empiric therapy and were continued on the same treatment regimen. Group 1B consists of two patients who were sensitive to CSE-1034 but failed to respond to CSE-1034 monotherapy clinically (showing no/less improvement) and were switched to CSE-1034 and colistin combination therapy. G2 patients, who were resistant to CSE-1034, were shifted to CSE-1034 + colistin combination therapy or meropenem after third day till the end of therapy [Figure 1].
Clinical success: The patient's response was considered as clinically successful when the patient recovered with either first-line empiric antibiotic therapy or a step down from the initial therapy.
Clinical failure: An individual case was defined as a clinical failure when the patient was switched to other antibiotics, or one or more antibiotics are added to the initial regimen.
First-line antibiotic therapy: It is defined as the regimen started at the beginning after admission to the hospital.
Second-line antibiotic therapy: It is defined as the addition of one or more antibiotics to the initial regime or a complete or partial replacement of the initial antibiotic with another parenteral antibiotic regime depending on microbial sensitivity results.
| » Results|| |
Patients and their demographic and clinical characteristics
The analyzed data of 150 patients suffering from various bacterial infections and treated with CSE-1034 showed that 59 (39.3%) patients diagnosed with HAP, VAP, and cUTI and meeting study inclusion criteria were enrolled in this retrospective study. Demographic parameters of all study patients, such as age, weight, height, respiration rate, pulse rate, systolic blood pressure, diastolic blood pressure, and temperature, are summarized in [Table 1]. Based on gender, the number of male patients was more when compared with females. Based on classification of infection type, UTI was the predominantly observed factor. Disease severity data analysis measured in terms of APACHE II score revealed that many patients had a score of <15. The most common comorbidities associated with patients at the time of hospitalization were diabetes mellitus, hypertension, chronic obstructive pulmonary disease, and anemia.[Table 2].
|Table 1: Demographic and baseline characteristics of all study participants (n=59)|
Click here to view
|Table 2: Percentage prevalence of pathogens isolated from different participants|
Click here to view
The main pathogens isolated were Escherichia More Details coli (29%), Acinetobacter baumannii (27%), and Klebsiella pneumoniae (18.6%).
Antibiotic sensitivity analysis
All the pathogens showed different susceptibility responses toward the tested antibiotics. CSE-1034 was the most active antibacterial agent with 86% susceptibility rates. About 78% isolates were susceptible to meropenem and 25% to Piptaz. The sensitivity pattern of colistin was nearly 100%. The highest susceptibility in terms of commonly isolated pathogens to CSE-1034 was observed in E. coli (94%), followed by A. baumannii (87.5%) and K. pneumoniae (81.8%) [Table 3].
|Table 3: In vitro antibiotic susceptibility testing of CSE-1034 for bacteria isolated from single organism infections|
Click here to view
Efficacy of antibiotic therapy
All the 59 patients included in this retrospective study were administered CSE-1034 empirically. The clinical responses observed in 96% of the patients were in concordance with the culture sensitivity results.
In all, 49 of 51 patients (G1A) identified with bacterial infections susceptible to CSE-1034 were completely cured with CSE-1034 monotherapy. The mean treatment duration in these 49 patients cured with CSE-1034 therapy was 9.4 ± 1.75 days [standard deviation (SD)]. Two of 51 patients (G1B) who showed a poor clinical response on the third day of empiric treatment despite being culture-sensitive were switched to CSE-1034 and colistin combination therapy and were reported cured.
Three patients who showed poor clinical response on the third day of empiric treatment and reported to be CSE-1034-resistant and meropenem-sensitive after culture sensitivity test were switched over to meropenem treatment regimen. Similarly, five patients whose conditions started deteriorating on the third day and were both meropenem- and CSE-1034-resistant received colistin as an add-on to the ongoing therapy [Table 4]. After the shift to alternate or combination therapy, the patients were reported to be completely cured. The mean treatment duration in patients cured with CSE-1034 and colistin combination therapy was 11.98 ± 2.55 days (SD) [Table 4]. Overall, it was found that 83% (49/59) of cases were cured with CSE-1034 monotherapy, 12% (7/59) cases with CSE-1034 and colistin combination therapy, and 5% (3/59) were cured with alternate meropenem therapy. Detailed clinical response in terms of indication and pathogen is listed in [Table 4]. Clinical efficacy analysis was further done on the basis of infection and pathogen type [Table 4].
|Table 4: Display of outcomes based on the type of infection and pathogen|
Click here to view
| » Discussion|| |
The current challenge in healthcare is to control the nosocomial or healthcare-associated infections that form the major cause of death and morbidity among hospitalized patients. Various surveys conducted by the WHO have shown that an average of 8.7% of patients admitted to hospital contract nosocomial infections globally.,, Comparing the figures in West and India, these nosocomial infections occur in around 10%–30% of patients admitted in India as against a decent 5% in the West.,,
UTIs, which represent one of the most common nosocomial infections, account for up to 40% of all healthcare-associated infections annually. Patients undergoing urological procedures, patients with indwelling urinary catheters, long-stay elderly patients, and patients with debilitating diseases are at high risk of developing nosocomial UTIs. HAP is the second most common nosocomial infection accounting for around 15% of hospital-acquired infections. Various studies have demonstrated that 70% of the patients hospitalized for at least 4 days have their oropharynx colonized with Gram-negative bacilli and this acts as a cornerstone for HAP. Other than the common risk factors that include weaker immune system, underlying illness, antibiotic exposure, invasive diagnostic, and therapeutic procedures, mechanical ventilation remains one of the prime causes for HAP and is specifically called as VAP. The empirical therapy for these infections is often chosen blindly and instituted much before the disease etiology is known. However, a serious concern about nosocomial infections is the rise in antimicrobial resistance among hospital pathogens mainly because of excessive and improper use of broad-spectrum antibiotics., The limited choice of antibiotics available and the growing antibiotic resistance has made it essential to identify novel molecules that could widen the spectrum of drugs for these infections. This study is an attempt to explore a novel drug CSE-1034 as a potential therapeutic option for the treatment of nosocomial infections including HAP, VAP, and UTI.
The study was conducted on 59 patients who were hospitalized in tertiary care centre and had acquired different types of nosocomial infections after getting admitted to hospital. The overall distribution pattern of these infections shows that UTI was the more predominant infection observed in 64% of the patients. This is in line with the previous studies that have reported UTI to be the most common nosocomial infection., The most common cause of these infections in terms of pathogen were E. coli (29%), A. baumannii (27%), and K. pneumoniae (18.6%). Consistent with our observations, various studies have reported that Gram-negative infections form the major fraction of nosocomial infections, particularly respiratory infections and UTI.,
As the infections acquired by patients were healthcare-associated where the risk of MDR infections is high, the patients were started empirically with CSE-1034. The choice of CSE-1034 as empirical therapy is well-supported by microbial susceptibility results.In vitro microbial antibiotic susceptibility testing of the pathogens isolated shows that 95% of patients were resistant to major classes of antibiotics. CSE-1034 was sensitive in 86% and meropenem was sensitive in 78% of the patients. The microbial susceptibility data clearly suggest that all the patients were suffering from MDR Gram-negative nosocomial infections. Various studies have documented a rise in MDR among pathogens causing nosocomial infections,, and this is mainly because of irrational and improper use of antibiotics. Resistance to various classes of antibiotics is because of the simultaneous expression of multiple resistance mechanisms including production of ESBLs, variety of drug efflux mechanisms, low-membrane permeability because of loss of porins, and increased target modification including changes in outer membrane proteins.
The clinical outcome observed was in concordance with susceptibility data. About 96% of patients sensitive to CSE-1034 responded well and were cured with CSE-1034 monotherapy. About 4% of patients sensitive to CSE-1034 and resistant to meropenem did not respond to CSE-1034 monotherapy. These patients were switched to CSE-1034 and colistin combination therapy and were reported cured. Around 5% of patients resistant to CSE-1034 were cured with meropenem treatment regimen, and 8.5% were cured with CSE-1034 and colistin combination therapy. Because all the patients responded well to this novel drug, CSE-1034 can be an empiric drug of choice for nosocomial infections. Using CSE-1034 as an empirical treatment can help us prevent the high mortality rate associated with inappropriate antimicrobial therapy (Martin and Ohlinger 2005).
The effectiveness of CSE-1034 can be attributed to the different mechanisms through which CSE-1034 targets various resistance pathways in bacteria. Various mechanisms include inhibition of conjugal spreading of resistance gene by chelating Mg2+ ions required for the activity of DNA relaxases, downregulation of MexAB-OprM and AcrAB-tolC efflux pumps, and chelation of Zn2+ ions required for the activity of MBLs., CSE-1034 is also believed to function as an antibiotic resistance breaker by disorganizing the extrapolymeric substance layer of biofilms and making the cell wall more porous and inhibit curli formation and bacterial adhesion.
Although a good number of patients were sensitive to meropenem which is the currently widely used drug to treat MDR infections, the most worrying part about carbapenems is the continuous rise in the number of MBL-producing organisms. Carbapenems were once successful therapy for ESBL-producing organisms and the most effective antimicrobial agents against Gram-negative bacterial infections. However, the indiscriminate use of this last resort drug has led to a rise in the development of resistance against this class of drug leading to its repeated failure, leaving us with few treatment options. MBL-producing bacterial strains can hydrolyze a wide range of antibiotics including beta-lactam antibiotics and carbapenems. A study conducted in 2010 has identified around 150 isolates of new MBLs. One of the isolates identified from India, Pakistan, and the United Kingdom has been named as NDM-1. The characteristic gene for MBL is carried on plasmids and spreads from one strain to another through horizontal gene transfer. Collectively, all these reports argue for the identification of alternate therapeutic molecules to lessen the burden on carbapenem family and prevent the development of resistance against them by restricting their usage.
Overall, the observations of our study strongly suggest that CSE-1034 can be a valuable empirical alternative to treat various MDR nosocomial infections including pneumonia and cUTI because of the various benefits associated with it, primarily the high sensitivity of MDR pathogens toward this drug. Second, all the patients responded well to this antibiotic. Third, and most importantly, its use can help spare carbapenems and prevent further rise in resistance against carbapenem family.
| » Conclusion|| |
In sum, from overall results of this retrospective study, it can be concluded that the use of CSE-1034 of ceftriaxone, sulbactam, and ethylenediaminetetraacetic acid is an effective option for the treatment of MDR nosocomial infections including pneumonia and cUTI.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| » References|| |
Cabrera-Cancio MR. Infections and the compromised immune status in the chronically critically ill patient: Prevention strategies. Respir Care 2012;57:979-90.
Rey C, Alvarez F, De-La-Rua V, Concha A, Medina A, Díaz JJ, et al.
Intervention to reduce catheter-related bloodstream infections in a pediatric Intensive Care Unit. Intensive Care Med 2011;37:678-85.
Bouassida K, Jaidane M, Bouallegue O, Tlili G, Naija H, Mosbah AT, et al.
Nosocomial urinary tract infections caused by extended-spectrum beta-lactamase uropathogens: Prevalence, pathogens, risk factors, and strategies for infection control. Can Urol Assoc J 2016;10:E87-93.
Gandra S, Barter DM, Laxminarayan R. Economic burden of antibiotic resistance: How much do we really know? Clin Microbiol Infect 2014;20:973-80.
Zimlichman E, Henderson D, Tamir O, Franz C, Song P, Yamin CK, et al.
Health care-associated infections: A meta-analysis of costs and financial impact on the US health care system. JAMA Intern Med 2013;173:2039-46.
Liu Q, Li X, Li W, Du X, He JQ, Tao C, et al.
Influence of carbapenem resistance on mortality of patients with Pseudomonas aeruginosa
infection: A meta-analysis. Sci Rep 2015;5:11715.
Lee Y, Choi H, Yum JH, Kang G, Bae IK, Jeong SH, et al.
Molecular mechanisms of carbapenem resistance in Enterobacter cloacae
clinical isolates from Korea and clinical outcome. Ann Clin Lab Sci 2012;42:281-6.
Chaudhary M, Mir MA, Ayub SG, Protocol 06 Group. Safety and efficacy of a novel drug elores (ceftriaxone + sulbactam + disodium edetate) in the management of multi-drug resistant bacterial infections in tertiary care centers: A post-marketing surveillance study. Braz J Infect Dis 2017;21:408-17.
Shameem M, Mir MA. Management of pneumonia and blood stream infections with new antibiotic adjuvant entity (ceftriaxone+sulbactam+disodium edetate)- A novel way to spare carbapenems. J Clin Diagn Res 2016;10:LC23-7.
Taneja N, Emmanuel R, Chari PS, Sharma M. A prospective study of hospital-acquired infections in burn patients at a tertiary care referral centre in North India. Burns 2004;30:665-9.
Boucher HW, Talbot GH, Bradley JS, Edwards JE, Gilbert D, Rice LB, et al.
Bad bugs, no drugs: No ESKAPE! An update from the Infectious Diseases Society of America. Clin Infect Dis 2009;48:1-2.
Guggenbichler JP, Assadian O, Boeswald M, Kramer A. Incidence and clinical implication of nosocomial infections associated with implantable biomaterials - Catheters, ventilator-associated pneumonia, urinary tract infections. GMS Krankenhhyg Interdiszip 2011;6:Doc18.
Cornejo-Juárez P, Vilar-Compte D, Pérez-Jiménez C, Ñamendys-Silva SA, Sandoval-Hernández S, Volkow-Fernández P, et al.
The impact of hospital-acquired infections with multidrug-resistant bacteria in an oncology Intensive Care Unit. Int J Infect Dis 2015;31:31-4.
Bjerklund Johansen TE, Cek M, Naber K, Stratchounski L, Svendsen MV, Tenke P, et al.
Prevalence of hospital-acquired urinary tract infections in urology departments. Eur Urol 2007;51:1100-11.
Peleg AY, Hooper DC. Hospital-acquired infections due to gram-negative bacteria. N Engl J Med 2010;362:1804-13.
Gaynes R, Edwards JR, National Nosocomial Infections Surveillance System. Overview of nosocomial infections caused by gram-negative bacilli. Clin Infect Dis 2005;41:848-54.
Sah MK, Shrestha RK, Mishra SK, Sherchand JB, Rijal B, Pokharel BM. Extended-spectrum-beta-lactamase producing multidrug resistant nosocomial bacterial isolates causing lower respiratory tract infection in tertiary care hospital. Nepal Eur Respir J 2014;44:P4698.
Caini S, Hajdu A, Kurcz A, Borocz K. Hospital-acquired infections due to multidrug-resistant organisms in Hungary, 2005-2010. Euro Surveill 2013;18: Pii: 20352.
Chaudhary M, Kumar S, Payasi A. a novel approach to combat acquired multiple resistance in Escherichia coli
by using EDTA as efflux pump inhibitor. J Microb Biochem Technol 2012;4:126-30. [Doi: 10.4172/1948-5948.1000082].
Chaudhary M, Kumar S, Payasi A. Role of CSE1034 in Escherichia coli
biofilm destruction. J Microb Biochem Technol 2013;5:54-8.
Meletis G. Carbapenem resistance: Overview of the problem and future perspectives. Ther Adv Infect Dis 2016;3:15-21.
Kuo SC, Chang SC, Wang HY, Lai JF, Chen PC, Shiau YR, et al.
Emergence of extensively drug-resistant Acinetobacter baumannii
complex over 10 years: Nationwide data from the Taiwan Surveillance of Antimicrobial Resistance (TSAR) program. BMC Infect Dis 2012;12:200.
Walsh TR. Emerging carbapenemases: A global perspective. Int J Antimicrob Agents 2010;36 Suppl 3:S8-14.
Kumarasamy KK, Toleman MA, Walsh TR, Bagaria J, Butt F, Balakrishnan R, et al.
Emergence of a new antibiotic resistance mechanism in India, Pakistan, and the UK: A molecular, biological, and epidemiological study. Lancet Infect Dis 2010;10:597-602.
[Table 1], [Table 2], [Table 3], [Table 4]