Carbapenems Sparing Antibiotics in the Management of Urinary Tract Infections caused by Multidrug Resistant Gram-Negative Organisms - A New Way to Control Growing Incidences of Carbapenem-Resistant EnterobacteriaceaeAbdud Samad1*, Hassan Harris1 and Mohammad Amin Mir2
2 Firoz Hospital and Research Center, Aligarh, Uttar Pradesh, India
Citation: Samad A, Harris H, Mir MA. Carbapenems Sparing Antibiotics in the Management of Urinary Tract Infections caused by Multidrug Resistant Gram-Negative Organisms - A New Way to Control Growing Incidences of Carbapenem-Resistant Enterobacteriaceae. J Basic Clin Pharma 2017;8:S34-S38.
This open-access article is distributed under the terms of the Creative Commons Attribution Non-Commercial License (CC BY-NC) (http://creativecommons.org/licenses/by-nc/4.0/), which permits reuse, distribution and reproduction of the article, provided that the original work is properly cited and the reuse is restricted to noncommercial purposes. For commercial reuse, contact [email protected]
Introduction: Urinary tract infections (UTIs) are the most common infection in humans. The retrospective study was aimed to analyze a new AAE (antibiotic adjuvant entity) of ceftriaxone+sulbactam with adjuvant disodium edetate as a carbapenem sparing drug in the management of UTIs caused by Escherichia coli. Methods: A retrospective review of patients treated for UTIs caused by Escherichia coli between January 2014 to April 2015 was conducted. Demographic characteristics, antibiotic therapy, length of hospital stay and clinical and microbiological outcome have been evaluated. Results: Data of 322 patients were reviewed. Of these, 112 patients who are diagnosed with UTI and having culture positive with E. coli were included in the study. Characterization of these isolates indicated that 48.2% were ESBL positive, 11.6% were MBL positive and 49.0% were found to be non ESBL/MBL. In microbiological evaluation, AAE appeared to be the most active drug against E. coli (89.3%) followed by meropenem (62.5%), imipenem plus cilastatin (58.03%) and piperacillin plus tazobactam (52.65%). Clinical success rate was 82.9% in AAE treated patients followed by 76% in meropenem, 71.4% in imipenem plus cilastatin and 63.1% in piperacillin plus tazobactam treated patients. Conclusion: The present study advocates that AAE can be considered as a drug of choice to carbapenem. Overall, this study results indicate approximately 6 to 11.5% superiority of AAE over penems (meropenem and imipenem plus cilastatin) and 19.8% to piperacillin plus tazobactam.
Ceftriaxone+sulbactam with adjuvant EDTA; AAE; E. coli; multidrug resistant; retrospective study; urinary tract infections
Urinary tract infections (UTIs) are the third most common infection in humans after respiratory and gastro-intestinal infections. They occur more commonly in women and as many as 50% of women face at least one episode of urinary tract infection in their lives, with 10% developing urinary tract infections yearly. UTIs are considered as complicated UTI when it is accompanied by calculi, infected cysts, renal/bladder abscesses, certain forms of pyelonephritis, spinal cord injury (SCI), catheters (structural abnormalities), diabetes, pregnancy (metabolic and hormonal abnormalities), transplant recipients (especially renal transplants) and patients with AIDS add to challenges related to impaired host response and sometimes these infections are co-hosted by pathogens like yeast/ fungi. Clinical presentation may vary from severe obstructive acute pyelonephritis with imminent urosepsis to a catheter-associated post-operative UTI, which might disappear spontaneously as soon as the catheter is removed.[4,5] The recurrence rate is high and according to studies about 25 % women experienced a second episode of UTI within 6 months of their first UTI.
In past decade the number of cUTIs due to resistant gram-negative bacteria has risen sharply, mainly due to the spread of ESBL-producing bacteria making treatment of cUTI problematic.[7,8] To overcome ESBLs resistance, carbapenem drugs have been introduced in clinical settings, although resistance to carbapenem has been reported globally that is mediated through production of carbapenems hydrolyzing enzymes called carbapenemases.[9-12] As a result of the increasing resistance towards antibiotics and drying antibiotic pipeline compelled us to look into opportunities for improving usage of the existing antimicrobial agents. Among numerous approaches, improvement of the existing antimicrobial agents through antibiotic adjuvant therapy is the most latest and successful.
Introduction of EDTA as an adjuvant for chelation and catalytic action to existing antibiotics has been seen as a ray of hope. A new AAE (ceftriaxone, sulbactam with adjuvant EDTA) has been reported to have proven efficacy in a wide range of infections.[14,15] This retrospective observational study has been performed to evaluate the best choice of antibiotic to be used empirically for the treatment of cUTI as an alternative to carbapenems.
Material and Methods
This retrospective study has been performed to evaluate and compare the use of new AAE in management of cUTI and co-relate its clinical efficacy with meropenem to support its use as carbapenem sparing drug. The study was performed at the tertiary care hospitals from January 2014 to April 2015.Being a retro-respective, it was not required to take approval of hospital ethics committee. Patient’s hospital case sheets and sample culture registers of the microbiology department were reviewed to short list all culture positive cases of cUTI. Only those cases of cUTI caused by Gram-negative microorganisms constituted the study population. Patient were classified as complicated UTIs if there were certain predisposing factors present. These factors include: obstructed urinary flow due to congenital causes, prostatic obstruction or urinary stones; incomplete bladder emptying due to anatomic (prostatic or urethral) or neurogenic (congenital or acquired spinal cord abnormalities) reasons; vesicoureteral reflux, foreign bodies in the urinary tract (instruments, catheters, drainage tubes); systemic illness such as diabetes; pregnancy and males participating in anal intercourse Figure 1.
Culture identification and susceptibility testing
Demographic analysis and antibiotic therapy
The detailed demographic and baseline characteristics of all patients including number of evaluable patients, age, weight, types of infections, severity which are analyzed in this study are given in [Table 1]. The patients have been treated with either meropenem (1.0 g, every 8 h), new any therapy (ceftriaxone sulbactam with adjuvant EDTA, 3.0 g every 12 h), imipenem plus cilastatin (500 mg QID) and piperacillin plus tazobactam (4.5 g every 8 hrs) intravenously. For those patients who has failed to respond to AAE, colistin therapy with a loading dose of 9 MIU followed by BD doses of 4.5 MIU has been used along with Elores.
The antibiotic therapy of all the patients included in this study has been initially started empirically based on the clinical symptoms and treating physicians decision and was continued or shifted to other therapy based on the in vitro microbiological susceptibility tests and clinical outcomes.
Clinical evaluation of patients
The clinical efficacy of the therapy was evaluated and classified as cured (resolution of clinical signs and symptoms or improvement not requiring further antibacterial therapy), or failure (persistence of clinical signs and symptoms or worsening in signs and symptoms that required alternative antimicrobial therapy after 72 h of treatment). The overall efficacy rate was defined as the proportion of the patients cured. Bacterial efficacy was evaluated based on the following four categories: complete eradication if elimination of the original causative pathogens, persistence if the original causative pathogens were repeatedly isolated, substitution if new organisms were isolated on repeated culture and re-infection if reappearance of the original causative pathogens after eradication and with clinical symptoms of infection.
Study design and demographic analysis
During this retrospective evaluation data of 322 patients having Gramnegative organisms in urine culture was reviewed. Of which, 114 culture were found to be of E. coli and meeting other criteria of the of study. The remaining culture (n=208) were of other pathogens and were excluded. On evaluation of susceptibility testing of these 114 isolates, only 112 isolates were observed to be susceptible to all drugs and were included in the study. There were chances of anaerobic associated infections (not detected in current study), hence metronidazole has been administered in patients of all groups as additional cover. All the 112 patients have been treated empirically by either AAE, meropenem, imipenem plus cilastatin or piperacillin plus tazobactam. The average age of patients was 55.23 ± 11.21 years [Table 1]. Acute pyelonephritis was reported in 33.0 % (n=37) cases, asymptomatic bacteriuria 16.9 % (n=19) cases, chronic prostatitis in 17.8 % (n=20), hydroureteronephrosis in 32.1 % (n=36). Diabetes mellitus was found to be the most common co-factor for complication in 24.1% cases and was handled as per standard of care.
|Age (y) mean (SD)||55.32 ( ± 6.52)||54.68 ( ± 7.25)||53.10 ( ± 6.60)||55.89 ( ± 6.77)|
|Sex (n) Male (%)||24 (51.06%)||12 (48.0%)||11 (52.38%)||10 (52.63%)|
|Sex (n) Female (%)||23 (48.94%)||13 (52.0%)||10 (47.62%)||9 (47.37%)|
|Weight (kg) mean (SD)||57.62 ( ± 7.90)||58.2 ( ± 8.95)||59.52 ( ± 6.41)||60.37 ( ± 8.39)|
|BMI (SD)||21.01( ± 1.71)||21.89 ( ± 1.72)||21.83 ( ± 1.82)||22.63 ( ± 2.17)|
|Diabetes duration (y) mean (SD)||4.03 ( ± 1.23)||4.15 ( ± 1.23)||4.00 ( ± 1.49)||4.00 ( ± 1.67)|
Table 1: Demographics characteristics of 112 evaluable patients treated during the study period.
Prevalence of ESBLs and MBLs
Our results showed that 48.2 % (54/112) isolates of E. coli were ESBL positive and 11.6% (13/112) were MBL positive.
In vitro antibiotic susceptibility
On evaluation of culture and sensitivity reports, only patients infected with E. coli were involved in the study. The results of in vitro antimicrobial susceptibility of AAE, imipenem plus cilastatin, meropenem and piperacillin plus tazobactam are presented in Table 3. According to the susceptibility results, AAE seemed to be the most active drug against E. coli with 89.3 % susceptibility followed by meropenem (62.5%), imipenem plus cilastatin (58.03%) and piperacillin plus tazobactam (52.65%).
|Pyelonephritis (n,%)||Complicated urinary Tract infections (n,%)|
|Single therapy||AAE||Empiric||20 (54.0)||19 (25.3)|
|Shifted||4 (10.8)||10 (13.3)|
|Meropenem||6 (16.2)||13 (17.3)|
|Imipenem plus cilastatin||3 (8.1)||12 (16.0)|
|Piperacillin plus tazobactam||1 (2.7)||11 (14.7)|
|Dual therapy||AAE+colistin||3 (8.1)||10 (13.3)|
Table 2: Indication wise cure rates of drugs.
|Name of drugs||Susceptibility|
|No of isolates||%|
|Meropenem||70 / 112||62.5|
Table 3: In vitro antibiotic susceptibility testing for E. coli.
Antibiotics treatment and their efficacy evaluation
A total of 112 patients have been included in this analysis out of which 47 have received AAE (G1), 25 meropenem (G2), 21 imipenem plus cilastatin (G3) and 19 piperacillin plus tazobactam (G4). Indication wise cure rates of different drugs are depicted in Table 2. In line with the hospital protocol, on third day of therapy, progress of the therapy has been evaluated in terms of the improvement in the clinical signs and symptoms and microbiological results. Patients with susceptible pathogens and clinical improvement has been continued on respective empirical therapies. Patients in AAE group showing no clinical improvement have been put on add on (dual) therapy with colistin. Patients of other groups with no improved clinical response have been shifted to AAE and observed for clinical signs of improvement. Those showed improvement have been retained on the therapy and those showing poor response were put on dual therapy with addition of colistin along with AAE.
In G1, 39 patients (82.9 %) have been clinically cured with complete bacteriological eradication. The mean duration of antimicrobial therapy for these patients is 6 days. While 8 patients (17.0%) did not respond to AAE on day 3 have been shifted to AAE+colistin combination therapy and all these have achieved clinical success. The average length of antibiotic treatment is 9 days.
With regard to G2, where 25 patients received meropenem, 19 patients (76%) were cured with average treatment duration of 8 days whereas 6 patients (24%) did not show response has been shifted to FDC from which 2 got cured and 4 have been put on dual therapy with average treatment duration 11 days. In G3, of 21 patients, 15 patients (71.4%) showed satisfactory clinical cure with imipenem plus cilastatin. The average treatment duration is 9 days while 6 patients (28.6%) who did not show clinical response at 3rd day have been shifted to AAE that resulted in clinical cure of 3 while remaining 3 have been put on dual therapy leading to increase in cure time to 12 days. In G4, for 19 patients who received piperacillin plus tazobactam, 12 patients (63.1%) responded well to achieve clinical cure. The average treatment duration is 9 days. On the other hand, 7 patients (36.8%) who did not show any clinical improvement on day 3 have been shifted to AAE and these patients get cured. The mean treatment duration for these 7 cured patients is 12 days [Table 4]
|Reason for failure
|Average treatment time||Mortality|
|Mono therapy with metronidazole|
with adjuvant EDTA (AAE)
|47||39 (82.9)||MBL positive+
|Meropenem||25||19 (76)||MBL positive||8||nil|
|Imipenem cilastatin||21||15 (71.4)||MBL positive||9||nil|
|Piperacillin tazobactam||19||12 (63.1)||Mixed ESBL+
with adjuvant EDTA (AAE)
|14||14 (100)||MBL positive||3+6||nil|
with adjuvant EDTA (AAE)+colistin
|13||13 (100)||Mixed ESB+MBL||3+6||nil|
Table 4: Summary of the clinically cured patients and reasons of failure of therapy.
Carbapenems are a class of beta-lactam antibiotics with broad spectrum of antibacterial activity and have been considered last resort antibiotics for many bacterial infections caused by ESBL-producers. However, in past few years, carbapenem-resistant due to carbapenemases and OprD expression have emerged among Enterobacteriaceae family. [10,20,21]
In order to combat carbapenem resistance, combination of beta-lactam and beta lactamase inhibitors have received much consideration as a carbapenem alternative drug.[22-24] However, only BL+BLI combinations did not exhibit significant activity against some ESBLs and MBL producing Gram negative organisms. Hence, AAE supplemented with antibiotic resistance breaker (proven for efficacy and safety) is in use at multiple multispecialty centers to treat the patients with infections caused by such organisms.[25,26] The retrospective evaluation has been carried out to collect adequate in support of this new AAE when used as carbapenem sparer.
In the current investigation, 112 patients of cUTI infected with E. coli and treated with AAE, meropenem, imipenem plus cilastatin and piperacillin plus tazobactam have been retrospectively analyzed for correlation between type of resistance (ESBL/MBL) and the clinical response. In UTI, E. coli has been reported to be most common [27,28] which corroborates with current investigation where 114/322 (35.4%) patients are found to be positive to E. coli.
On antimicrobial susceptibility data evaluations 89.3 % of E. coli were found to be sensitive to AAE, followed by meropenem (62.5%), imipenem plus cilastatin (58.03%) and piperacillin plus tazobactam (52.6%). The greater susceptibility of E. coli to AAE and lesser susceptibility of comparator drugs is consistent with previous studies. [14,29]
With regard to clinical success rate, the overall clinical success rate in AAE treated patients is 82.3% compared to 76% in meropenem, 71.4% in imipenem plus cilastatin and 63.1% in piperacillin plus tazobactam. Overall, AAE is showing 6 to 11.5 % higher clinical success rates compared to penems (meropenem and imipenem plus cilastatin) and 19.8 % to piperacillin plus tazobactam. The greater cures rates with this new AAE is likely to be associated with efflux over expression and MBL genes in pathogens to which other drugs fail to respond. AAE has been shown to be more effective against MBLs and AcrAB-tolC efflux positive isolates and mixed isolates.[29-31] All these factors may contribute to make it more efficacious against multi-drug resistant pathogens. The clinical success rates achieved with AAE is similar to a phase III study conducted where clinical cure rates with AAE was 83.33%. Several animal studies also indicated promising in vivo efficacy of AAE.[32,33]
In contrast, lesser cure rates of comparator drugs may be probably due to less activity of these drugs against biofilm producing MBLs, AcrABtolC positive isolates.[29,34] This retrospective study revealed 24 % failure cases with meropenem, 28.5% in imipenem plus cilastatin and 36.8 % in piperacillin plus tazobactam treated group which can be co-related with failure of these drugs to respond to efflux, biofilm and MBL genes along with false susceptibility reported earlier.
In conclusion, our data advocates that AAE of ceftriaxone + sulbactam with adjuvant disodium edetate can be considered as an alternate option for Carbapenem as sparing drug. Overall, our results indicate around 6 to11.5 % superiority of new AAE alone over penems (meropenem and imipenem plus cilastatin) and 19.8 % to piperacillin plus tazobactam.
Our technical officer for helping us with data entry.
Financial support and sponsorship
Conflict of Interest
- Vanuzzo D, Pilotto L, Mirolo R, Pirelli S. Cardiovascular risk and cardiometabolic risk: an epidemiological evaluation. G Ital Cardiol 2008;9:6S-17S.
- Lu Y, Hajifathalian K, Ezzati M, Woodward M, Rimm EB, Danaei G. Global Burden of Metabolic Risk Factors for Chronic Diseases Collaboration (BMI Mediated Effects), Metabolic mediators of the effects of body-mass index, overweight, and obesity on coronary heart disease and stroke: a pooled analysis of 97 prospective cohorts with 1·8 million participants. Lanc 2014; 383:970-83.
- Gregorio-Arenas E, Ruiz-Cabello P, Camiletti-Moirón D, Moratalla-Cecilia N, Aranda P, López-Jurado M, et al. The associations between physical fitness and cardiometabolic risk and body-size phenotypes in perimenopausal women. Maturitas 2016;92:162-7.
- Li Z, Guo X, Liu Y, Zhang N, Chang Y, Chen Y, et al. Metabolism rather than obesity is associated with ischemic stroke: a cross-sectional study in rural Northeastern China. Springerplus 2016;5:1419.
- Nangia R, Singh H, Kaur K. Prevalence of cardiovascular disease (CVD) risk factors. Med J Armed Forces Ind 2016; 72:315-9.
- Eckel RH, Cornier MA. Update on the NCEP ATP-III emerging cardio metabolic risk factors. BMC Med 2014;12:115.
- Rey-López JP, de Rezende LF, Pastor-Valero M, Tess BH. The prevalence of metabolically healthy obesity: a systematic review and critical evaluation of the definitions used. Obesity Reviews 2014;15:781-90.
- Blüher M. The distinction of metabolically 'healthy' from 'unhealthy' obese individuals". Current Opinion in Lipidolo 2010;21:38-43.
- Bluher M. Mechanisms in endocrinology: Are metabolically healthy obese individuals really healthy? Eur J Endocrin 2014;171:R209–R19.
- Duncan GE. The “fit but fat” concept revisited: population-based estimates using NHANES. Int J Behav Nutr Phys Act 2010;7:47.
- Stefan N, Häring HU, Hu FB, Schulze MB. Metabolically healthy obesity: epidemiology, mechanisms, and clinical implications. Lancet Diabetes Endocrinol 2013;1:152-62.
- Wildman RP, Muntner P, Reynolds K, McGinn AP, Rajpathak S, Wylie-Rosett J, et al. The obese without cardio metabolic risk factor clustering and the normal weight with cardio metabolic risk factor clustering: prevalence and correlates of 2 phenotypes among the US population (NHANES 1999-2004). Arch Intern Med 2008;168:1617-24.
- Galyfos G, Geropapas GI, Kerasidis S, Sianou A, Sigala F, Filis K, et al. The effect of body mass index on major outcomes after vascular surgery. J Vasc Surg 2016.
- Nagarajan V, Kohan L, Holland E, Keeley EC, Mazimba S. Obesity paradox in heart failure: a heavy matter. ESC Heart Fail 2016;3:227-34.
- Grandin EW, Wand A, Zamani P, Rame JE, Verdino RJ. Relation of Body Mass Index to Long-Term Survival after Cardiac Resynchronization Therapy. Am J Cardiol 2016.
- Lechi A. The obesity paradox: is it really a paradox? Hypertension. Eat Weight Disord 2016.
- Berezin A. Metabolomics in Heart Failure Patients: Hype and Hope. J.Biomark 2016;2 :e21-e3.
- Yu D, Moore SC, Matthews CE, Xiang YB, Zhang X, Gao YT, et al. Plasma metabolomic profiles in association with type 2 diabetes risk and prevalence in Chinese adults. Metabolomics 2016.
- Qiu G, Zheng Y, Wang H, Sun J, Ma H, Xiao Y, et al. Plasma metabolomics identified novel metabolites associated with risk of type 2 diabetes in two prospective cohorts of Chinese adults. Int J Epidemiol 2016.
- Zhao J, Zhu Y, Hyun N, Zeng D, Uppal K, Tran VT, et al. Novel metabolic markers for the risk of diabetes development in American Indians. Diabetes Care 2015;38:220-7.
- Carter TC, Rein D, Padberg I, Peter E, Rennefahrt U, David DE, et al. Validation of a metabolite panel for early diagnosis of type 2 diabetes. Metabol 2016;65:1399-408.
- Lu Y, Wang Y, Ong CN, Subramaniam T, Choi HW, Yuan JM, et al. Metabolic signatures and risk of type 2 diabetes in a Chinese population: an untargeted metabolomics study using both LC-MS and GC-MS. Diabetologia 2016;59:2349-59.
- Khan UI, Wang D, Thurston RC, Sowers M, Sutton-Tyrrell K, Matthews KA, et al. Burden of subclinical cardiovascular disease in “metabolically benign” and “at-risk” overweight and obese women: the Study of Women’s Health Across the Nation (SWAN). Atherosclerosis 2011;217:179-186.
- Prince RL, Kuk JL, Ambler KA, Dhaliwal J, Ball GD. Predictors of metabolically healthy obesity in children. Diabet Care 2014;37:1462-68.
- Berezin AE. Endothelial progenitor cells dysfunction and impaired tissue reparation: the missed link in diabetes mellitus development. Diabetes & Metabolic Syndrome: Clinic Res & Rev 2016.
- Berezin AE. Biomarkers for cardiovascular risk in diabetic patients. Heart 2016.
- Asahara T. Endothelial progenitor cells for vascular medicine. Yakugaku Zasshi 2007; 127:841-5.
- Asahara T, Murohara T, Sullivan A, Silver M, van der Zee R, Li T, et al. Isolation of putative progenitor endothelial cells for angiogenesis. Sci 1997;275:964-7.
- Hur J, Yoon CH, Kim HS, Choi JH, Kang HJ, Hwang KK, et al. Characterization of two types of endothelial progenitor cells and their different contributions to neovasculogenesis. Arterioscler Thromb Vasc Biol 2004;24:288-93.
- Berezin A. Epigenetic Mechanisms of Endothelial Progenitor Cell Dysfunction. J Clin Epigenet 2016;2:24-6.
- Berezin A. “Impaired Phenotype” of Endothelial Cell-Derived Microparticles: Causality Factor Contributed the “Vascular Competence” in Diabetes and Metabolic Syndrome? Diabetes Res Treat Open Acc 2016;3:133-6.
- Fadini GP, de Kreutzenberg SV, Coracina A, Baesso I, Agostini C, Tiengo A, et al. Circulating CD34+ cells, metabolic syndrome, and cardiovascular risk. Eur Heart J 2006;27: 2247-55.
- Berezin AE, Kremzer AA, Berezina TA, Martovitskaya YV, Gronenko EA. Association between serum osteoprotegerin level and numerous of circulating endothelial-derived and mononuclear-derived progenitor cells in patients with metabolic syndrome. Data in Brief 2016; 8:717-22.
- Berezin AE, Samura TA, Kremzer AA, Berezina TA, Martovitskaya YV, Gromenko EA, et al. An association of serum vistafin level and number of circulating endothelial progenitor cells in type 2 diabetes mellitus patients. Diabetes Metab Syndr 2016.
- Berezin AE. Metabolic memory phenomenon in diabetes mellitus: Achieving and perspectives. Diabetes Metab Syndr 2016;10:S176-83.