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 Table of Contents  
ORIGINAL ARTICLE
Year : 2016  |  Volume : 19  |  Issue : 1  |  Page : 5-10

A retrospective comparative study to evaluate the use of a new beta-lactam + beta-lactamase inhibitor (ceftriaxone + sulbactam + disodium edetate) in comparison to meropenem in the management of gram-negative bacterial sepsis


1 Department of Critical Care and Respiratory Medicine, Metro Heart Institute with Multispeciality, Faridabad, Haryana, India
2 Department of Critical Care Medicine, Metro Heart Institute with Multispeciality, Faridabad, Haryana, India
3 Department of Pathology, Metro Heart Institute with Multispeciality, Faridabad, Haryana, India
4 Department of Microbiology, Metro Heart Institute with Multispeciality, Faridabad, Haryana, India

Date of Web Publication17-Dec-2015

Correspondence Address:
Vijay Kumar Agrawal
House No 966, First Floor, Sector 37, Faridabad, Haryana
India
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DOI: 10.4103/1119-0388.172068

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  Abstract 

Introduction and Objective: Gram-negative bacterial sepsis and anti-microbial resistance are global health concerns. The present study is a comparative retrospective analysis of the outcome of two antibacterial therapies (Ceftriaxone + Sulbactam + adjuvant Disodium edetate [FDC] and Meropenem) used for management of patients suffering from gram-negative bacterial sepsis. Materials and Methods: Both the therapies (FDC or Meropenem) were initiated empirically on the basis of clinical presentation of the patients and treating physician's decision and continued based on the results of the in vitro microbiological susceptibility testing pattern and clinical outcome. Results: 70 patients with known Gram-negative bacterial infections showing sensitivity to FDC and Meropenem were included in the study. Fifty-seven (81.42%) out of 70 cultures isolated from the patients showed susceptibility towards FDC, whereas the isolates showed comparatively lower susceptibility (45 [64.28%]) towards Meropenem. Twenty (54.05%) out of 37 patients treated with FDC were cured, while the remaining patients achieved clinical success with FDC + Colistin combination therapy. On the other hand, only 11 (33.33%) out of 33 patients to whom Meropenem was given empirically were cured, and the remaining 22 patients required Meropenem and Colistin combination therapy to achieve clinical cure. Conclusion: This new FDC exhibits better antimicrobial susceptibility than Meropenem and a better efficacy in gram-negative sepsis management. This new FDC in combination with Colistin can be used to treat severe sepsis patients, which often fails to respond to monotherapy. This new FDC and Colistin can be an effective alternate therapy to Meropenem and Colistin.

Keywords: Antibiotic adjuvant entity, carbapenems, colistin, drug resistance


How to cite this article:
Agrawal VK, Bansal A, Pujani M, Jawa M, Mahajan P, Jain A. A retrospective comparative study to evaluate the use of a new beta-lactam + beta-lactamase inhibitor (ceftriaxone + sulbactam + disodium edetate) in comparison to meropenem in the management of gram-negative bacterial sepsis. Trop J Med Res 2016;19:5-10

How to cite this URL:
Agrawal VK, Bansal A, Pujani M, Jawa M, Mahajan P, Jain A. A retrospective comparative study to evaluate the use of a new beta-lactam + beta-lactamase inhibitor (ceftriaxone + sulbactam + disodium edetate) in comparison to meropenem in the management of gram-negative bacterial sepsis. Trop J Med Res [serial online] 2016 [cited 2019 Jul 18];19:5-10. Available from: http://www.tjmrjournal.org/text.asp?2016/19/1/5/172068


  Introduction Top


Gram-negative bacterial infections are a serious health concern, especially antimicrobial resistance, which is fast becoming a global health concern with the rapid increase in multi-drug resistant (MDR) organisms.[1] The abundant and often inappropriate use of broad-spectrum antibiotics contributes to the emergence of these MDR strains.[2] The emergence and proliferation of these highly-resistant bacteria are particularly concerning due to the limited number of antimicrobial agents available for use against these pathogens.[3] Despite recent advances in critical care medicine, the mortality of sepsis in the intensive care unit (ICU) remains high.[4],[5] Cephalosporin along with other beta-lactam antibiotics were the drugs of choice for the management of sepsis initially, which later shifted to carbapenems due to emergence of resistant strains.[6],[7] The carbapenems are stable against most of beta-lactamases produced by these resistant strains, and have displayed considerable efficacy in sepsis management.[7],[8] However in the recent past, there has been a continuous rise in carbapenem resistance amongst gram-negative bacteria throughout the world, including India.[9],[10],[11],[12],[13],[14]

Due to the rise in resistance towards the available antibiotics, new regimes are advocated for the management of sepsis. The use of adjuvant along with beta-lactamase and beta-lactamase inhibitor combinations is one such new approach to treat these multi drug resistant bacterial infections.[15] Antibiotics adjuvants are active molecules, preferably with non-antibiotic activity, that in combination with antibiotics, enhance the antimicrobial activity of the latter. These compounds can function either by reversing resistance mechanism in naturally sensitive pathogens, or by sensitizing intrinsic resistant strains. This new FDC (Ceftriaxone + Sulbactam + adjuvant Disodium Edetate) is one such novel Antibiotic Adjuvant Entity (AAE) approved by the Drug Controller General of India (DCGI), and increasingly used in Indian hospitals. Various reports of the in-vitro susceptibility studies [15] hint towards the possibility of this new FDC to overcome the hurdle of gram-negative bacterial resistance clinically. If effective in-vivo clinical success is achieved by this new FDC, it can be a potent carbapenem-sparing antibiotic.

The present study is a comparative retrospective analysis of the clinical and microbiological efficacy of this new FDC and meropenem used as mono-therapy or combination therapy along with Colistin in the management of gram-negative sepsis.


  Materials and Methods Top


Patients and antibiotic therapy

The present retrospective study was conducted by analyzing the data from a 150 bedded tertiary care hospital, Delhi-NCR, India between October 2012 to December 2013. The data of 86 patients from the intensive care unit (ICU), suffering from sepsis (abdominal, respiratory and urosepsis) caused due to gram-negative bacteria were evaluated. After in vitro antimicrobial susceptibility testing reports were received, the patient's exclusion and/or inclusion criteria were determined. Among 86 evaluated patients, 70 clinically cured patients, showing sensitivity towards the respective empirical therapies were considered for the study. However, 16 patients with culture negative infections or with cultures exhibiting resistance towards the respective antibiotics and patients who expired during the course of treatment were excluded from the study. The variables of the patients like age, infection type, source of infection, causative pathogen, dosage, and regime of antibiotic therapy were evaluated. The selection of empirical therapy was based on the clinical presentation of the patients as well as the decision of primary physician. Among various classes of drugs, B-lactam is one to the most frequently prescribed antimicrobial drugs for the treatment of such infections. However, in recent years, rise in resistance to B-lactam drugs has been noticed because of the extended spectrum B-lactamases (ESBLs) enzymes, which hydrolyze most of the B-lactam antibiotics. Although, carbapenems seemed to be the best options as empirical therapy (especially in gram negative sepsis), emergence of metallo-beta lactamases restricted the use of carbapenems. It's high time to look ahead for newer possibilities. The in vitro, pre-clinical, microbiological, and molecular studies demonstrated comparative effectiveness of FDC with piperacillin + tazobactam and Cefoperazone + salbactam combination.

FDC was administered in a dose of 3.0 g/12 h intra-venous infusion over 90 minutes, while 1 g of meropenem was given every 8 h. The dose was selected based on the T > MIC, concentration of Ceftriaxone which was higher than the minimum inhibitory concentration (MIC) for most of the gram positive and gram negative bacteria, indicating that twice daily dose per day is sufficient to treat the disease caused by these organisms. Each dose of 3.0 gm FDC contains Ceftriaxone sodium IP equivalent to Ceftriaxone 2000 mg, Sulbactam sodium USP equivalent to Sulbactam 1000 mg and Disodium edetate IP 74 mg. Dose of FDC was reduced to half in patients with pre-terminal renal failure (creatinine clearance > 10 ml per minute). The duration of therapy varied according to the course of the disease. As with antibiotic therapy in general, administration of FDC or meropenem was continued for a minimum of 48-72 h after the patient became afebrile or evidence of bacterial eradication had been obtained. However for Colistin, a loading dose of 9 MIU, followed by BID doses of 4.5 MIU were used. Colistin was dissolved in 100 ml of normal saline and administered as an intravenous infusion over 15 min. Doses of Colistin and meropenem were reduced in patients with renal dysfunction, as per creatinine clearance.

On retrospective evaluation of the data based on antibiotic administration, the treated patients were categorized into two groups, i.e. Group G1 - patients (n = 37) in whom FDC was used empirically and Group G2 - patients (n = 33) in whom Meropenem was opted for as an empirical drug. The progress of the empirical therapy, measured in terms of improvement in the signs and symptoms and bacterial sensitivity was evaluated after 3 days. The patients showing bacterial sensitivity and clinical improvement were continued with the same antibiotic, while for those, who failed to respond (no improvement), Colistin was used as an additional therapy (add on therapy) [Figure 1].
Figure 1: Overview of the study design

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In vitro microbial antibiotic susceptibility testing

Antimicrobial susceptibility testing of the pathogens isolated from the patients was done by Kirby-Bauer disk diffusion method as recommended by the Clinical Laboratory Standards Institute.[16] Ceftriaxone + Sulbactam + EDTA disks (55μg) and Colistin disks (10µg) were procured from HiMedia (Mumbai, India) and used in the study. Sensitivity of isolated organisms against antibiotics were reported as sensitive (S), Intermediate (I), or resistant (R) based on the zone diameters as per HiMedia. For the remaining antibiotics, susceptibility testing was performed in an automated fashion using the ATB READER (Biomerieux).

Clinical analysis of patients

The patients' clinical status associated with gram-negative bacterial sepsis was evaluated based on the initial clinical signs and symptoms. The laboratory parameters like WBC count, hemoglobin, platelet count, Liver Function Test and Renal Function Test were also evaluated. Broncho-alveolar lavage, Endo-Tracheal secretions, urine or blood samples from the patients were tested for the diagnosis of causative pathogens. All the patients considered for the study were under continuous monitoring for clinical improvement. Signs and symptoms along with laboratory parameters were evaluated initially and 3 days after the onset of the empirical treatment. Associated co-morbidities and severity of illness were also considered to ensure a comparative evaluation of both the groups. Clinical outcome of the therapy was adjudged at the end of the treatment and was classified as cured (absence of sepsis signs and symptoms), improved (improvement in local and systemic signs and symptoms), and failure (no improvement or deterioration of the existing signs and symptoms).


  Results Top


Patients and demographic characteristics

The demographic characters of 70 patients, who were considered for the retrospective evaluation, are depicted in [Table 1]. The age of the patients was between 39-81 years with mean age being 58.24 ± 12.92 (S.D.) years. On the basis of clinical and laboratory evaluation, the origin/site of sepsis revealed patients having three types of sepsis: Abdominal, respiratory and urosepsis. Amongst these, respiratory sepsis was the predominant infection, accounting for 44.28% (31) patients, followed by urosepsis and abdominal sepsis in 26 (37.14%) and 13 (18.57%) patients respectively [Table 1]. Bacterial culture reports revealed that the highest number of patients (27 [38.57%]) had an Escherichia coli infection, which was closely followed by Klebsiella spp. infection i.e. 22 (31.42%). However, Acinetobacter spp. and Pseudomonas spp. were diagnosed in comparatively lesser number of patients (10 [14.28%] and 11 [15.71%] respectively) [Table 1].
Table 1: Demographic characteristics of the patients treated during the study period

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In vitro microbial antibiotic susceptibility testing

The in vitro susceptibility results for isolated pathogens against the considered drugs are summarized in [Table 2]. Fifty-seven (81.42%) out of 70 organisms isolated from the patients were susceptible to FDC, while the remaining 13 cultures showed intermediate resistance to it. However the isolates showed comparatively higher resistance to meropenem, with only 45 (64.28%) isolates exhibiting susceptibility. Highest susceptibility towards FDC was observed with Escherichia coli (85.18%)followed by Pseudomonas spp. (81.81%), Acinetobacter spp. (80%) and Klebsiella spp. (77.27%). Similar pattern of susceptibilities were observed for meropenem; highest (74.07%) with Escherichia coli while least (54.54%) with Klebsiella spp. [Table 2].
Table 2: In-vitro antibiotic susceptibility testing for the isolated bacteria

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Efficacy of antibiotic therapy

In group G1, patients who were identified with FDC susceptible bacterial infection with signs of clinical improvement were continued with the same antibiotic. Twenty (54.05%) out of 37 patients showed clinical improvement with mean treatment duration of 9.15 days ± 1.22 (S.D.) with FDC mono therapy. The remaining 17 (45.95%) patients, who failed to respond to FDC monotherapy, were shifted to the FDC + Colistin combination therapy, to which all the 17 patients responded well. The mean treatment duration for these 17 cured patients with combination therapy was 11.29 days ± 1.10 (SD). On the other hand, only 11 (33.33%) out of 33 patients who were on empirical Meropenem treatment were cured with mean treatment duration of 9.27 days ± 0.78 (S.D.). The remaining 22 patients who failed to respond to Meropenem monotherapy were given Meropenem + Colistin combination therapy. All the 22 patients showed clinical improvement with this combination therapy with mean treatment duration of 11.90 days ± 1.23 (S.D.). The other supporting care given was the same in both the groups as per patients' needs.


  Discussion Top


Bacterial sepsis is a major cause of morbidity and mortality worldwide. Gram-negative bacteria produce sepsis and septic shock via the release of the cell-wall component known as endotoxin (lipopolysaccharide). The lipid-A moiety, common to all gram-negative bacteria, is immunogenic and appears to account for many of the biological effects of endotoxin.[17] Inappropriate antimicrobial therapy in severe sepsis is associated with a higher mortality rate.[18] Therefore, choice of empirical antibiotic therapy should be based on the underlying lesion, the most likely causative organism and the local prevalence of resistance pattern.[19] The present data reviewed, represents 70 patients suffering from sepsis patients cured with either FDC or meropenem empirical therapies.

Antimicrobial susceptibility testing results for the tested drugs against the isolated pathogens reveals higher susceptibilities in cases of FDC (81.42%) as compared to meropenem (64.28%). A similar trend was observed in the clinical outcome of the therapy. Clinical cure rate of 54.05% observed in Group G1 patients (FDC-treated group) is significantly higher than cure rates of 33.33% in Meropenem treated group (Group G2). However there is a considerable difference in the in-vitro susceptibility testing and the clinical outcome with comparatively lower proportion of patients achieving clinical cure. This difference may be attributed to the high percentage of either false in vitro susceptibility results and/or failure of the drug to eradicate the bacterial infection in vivo. Chaudhary et al. (2013) conducted a multicenter study on 297 patients of lower respiratory and urinary tract infections and observed better clinical cure rate with FDC in comparison to Ceftriaxone alone. They also observed that FDC appeared to be highly susceptible to isolates positive with MBL genes NDM-1, VIM-1, KPC-2 AND IMP-1.[20] The same authors also observed better outcomes with FDC in comparison to Ceftriaxone in skin and skin structures infections (SSSIs) and bone and joint infections (BJIs) in ESBL and MBL producing gram-positive and gram-negative pathogen.[21]

The results of our study are contradictory to the results of the previous study carried out by Chytra et al.,[22]whoreported higher clinical cure rates (74.3%) with Meropenem. This increased clinical failure rate strongly advocates increased Carbapenem-resistance rates attributed to various resistance mechanisms acquired, along with carbapenamases (MBL) production. One such resistance mechanism is over-expression of efflux pumps like MexAB-OprM efflux system in Pseudomonas spp. (specific to meropenem resistance),[23] AcrB efflux pumps in Escherichia coli,[24] AcrAB efflux pumps in Klebsiella spp.[25] and AdeABC type efflux pumps identified in Acinetobacter spp.[26] Comparatively superior efficacy (clinical cure rates) of FDC as compared to meropenem might be due to the proven effect of FDC as an efflux pump inhibitor.[27] On the other hand, the patients who failed to respond to either FDC or meropenem, achieved clinical cure when Colistin was given along with the empirical therapy. Previous results suggested that combination therapy was superior to monotherapy for severely ill patients, particularly those in septic shock.[28] Definitive combination therapy including two antibiotics to which the bacteria are susceptible has been suggested to improve the clinical outcome, as compared to monotherapy for critically ill patients with severe infections of Pseudomonas spp.[29],[30] Colistin demonstrates concentration-dependent bacterial killing, suggesting that higher doses should be administered less frequently to achieve higher peak concentrations. It is likely that a low initial concentration (subtherapeutic concentrations) would be suboptimal in killing the bacteria,[31] especially in critically ill patients, where an immediate effect is important.[32] The loading dose of Colistin was administered at 9 million units, with subsequent maintenance doses of 4.5 MU administered every 12 h.[33]

The action of Colistin is by a detergent-like mechanism, interfering with the structure and function of the outer membrane of bacteria resulting in increased permeability.[34],[35] The benefits of Colistin in infection management outweigh the toxicity risks and that is efficiently managed with appropriate dosing regimen. Thus, Colistin was selected to be used as a combination therapy along with both FDC and meropenem. The increased efficacy (clinical cure rates) of this combination therapy might be due to synergy between the antibiotics. Even though the exact mechanism of synergism is not known, we may assume that Colistin increases the permeability of FDC and meropenem through the bacterial outer membrane by a detergent mechanism. This mechanism can counteract acquired resistance mediated by decreased antibiotic permeability (e.g. porin loss), and enables antibiotics which fail to act in case of severe bacterial infections like sepsis.[36] The clinical success results obtained with the FDC and Colistin combination therapy are justifiable by the support of the previous reports wherein, combination therapy for suspected sepsis and severe gram-negative infections typically includes a broad-spectrum beta-lactam and Colistin.[28],[37],[38],[39]


  Conclusion Top


In conclusion, the present study represents the comparative susceptibility status of Meropenem and FDC amongst gram-negative pathogens isolated from cases of sepsis. The present study highlights increased Carbapenem resistance amongst the pathogens responsible for different types of sepsis. The results of the present study favor the use of FDC for its use as a substitute for Meropenem (both in mono and combination therapies) to treat sepsis caused by carbapenem-susceptible and intermediately-resistant gram-negative bacteria. This retrospective analysis has limitations; hence we need more prospective studies with a larger number of subjects to establish the efficacy of FDC in gram-negative sepsis.

 
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