Antibiotic Adjuvant Therapy for Multi-Drug Resistant Carbapenemases Producing Klebsiella pneumoniae Associated Sepsis: A Case Study

Rising resistance and spread of K. pneumoniae strains, create great concerns in treating sepsis patients due to high incidence of mortality and morbidity. The current study is a case of a 20-year-old male with sepsis and bilateral lung lesions infected with Multi-Drug Resistant (MDR) carbapenemase producing K. pneumoniae (KPC) showing resistance to carbapenem and polymyxin. Based on sensitivity report, patient was put on antibiotic adjuvant: Elores (ceftriaxone, sulbactam, disodium edetate) along with fluconazole for 10 days. Elores was instituted with remarkable recovery and patient was discharged.

A 20-year-old male patient who was infected by KPC-producing K. pneumoniae was transferred to the Emergency Department of Government Medical College and Hospital, Chandigarh from a private hospital (Chandigarh), with chief complaints of fever and cough since one month. Patient had taken treatment of second generation cephalosporins and aminoglycosides from private clinics but did not respond well which further deteriorated his condition and progressed to sepsis. Patient was on initial treatment of meropenem and teicoplanin when admitted to emergency Department of Government Medical College and Hospital, Chandigarh, but there were no signs of improvement even after 7 days of treatment.

Overall condition of the patient was poor with hypo-tension, hypothermia, tachycardia, tachypnea, leucocytosis and anaemia. Vital signs were, blood pressure-70/40mmHg, pulse-116bpm, Respiratory rate- 22 breaths per min, temperature-36.4°C. Laboratory reports revealed total leukocyte count of 430000/mm, haemoglobin 11.1g/dl and haematocrit 34.8%. Patients C-reactive protein level was deranged to 70mg/l and procalcitonin level were up to 10ug/l. Based on clinical presentation and laboratory reports patient was diagnosed as sepsis and immediately transferred to intensive care unit and resuscitated. Blood sample was taken for routine Investigations, culture and sensitivity. Chest X ray was advised and revealed bilateral cavitation in both lungs. Patient was put on colistin with fluconazole and linezolid but did not respond to the therapy. Laboratory culture and sensitivity reports revealed MDR K. pneumoniae with resistance to carbapenems, colistin and sensitivity to Elores. Thus initial antibiotic therapy was stopped and patient was put on Elores 3g b.i.d dose with fluconazole for 10 day along with other supportive therapy. Patient’s condition improved gradually. Repeat laboratory test revealed normalized leukocyte count with reduced CRP (8mg/l) and procalcitonin levels (<0.25ug/l). Patient was haemodynamically stable and shifted to medicine ward for further monitoring and treatment. Patient was put on oral antibiotics and discharged on 17^th day post admission with advice for regular follow-up.

Gram-negative bacteria have often been involved in the pathogenesis of sepsis [1]. Among Gram-negative pathogens, Klebsiella pneumoniae has increasingly been associated with hospital infections, especially in the Intensive Care Unit (ICU). Resistance of K. pneumoniae strains to broad-spectrum antibiotics, including carbapenems, is a matter of great concern [2]. The best therapeutic approach to KPC-producing organisms has yet to be defined as last resort of antibiotics like penem and colistin getting resistant to KPC. There are ongoing efforts to find out and try strategies which would improve outcome of this population [3].

Sepsis is an increasingly common cause of morbidity and mortality in critically ill patients. Despite advancement in surgical and critical care management, the projection of sepsis and subsequent multiple organ dysfunction has not improved mainly due to escalating resistance. Mortality rate among patients with severe sepsis and septic shock has been observed between 25% to 30% and 40% to 70% respectively, with increase in sepsis at an estimated annual rate of 1.5% [4]. Moreover, in a study from New Delhi, the ICU mortality with sepsis was reported 45.6% in young patients (< 60 years of age) [5]. Klebsiella species are common pathogens in ICUs, with infection of the lung, urinary tract and abdomen [6].

MDR, KPC producing K. pneumoniae due to inappropriate selection of antibiotic is a growing concern worldwide [3]. Carbapenems have been considered to be the last-line antimicrobial agents against MDR Gram-negative Bacteria, while recently increasing emergence of Carbapenemase-Producing Enterobacteriaceae (CPE) has been reported worldwide [7]. There are many carbapenemases involved in CPE isolates, in which carbapenemase producing K. pneumoniae plays a vital role in health care-associated infection [8]. In India, the prevalence of KPC producing K. pneumoniae is reported up to 33.3% [6].

Infections caused by KPCs have very limited options for treatment and often require the use of polymyxins, which fell into disuse in the 1970s due to high rates of nephrotoxicity [8]. An early diagnosis of sepsis followed by broad-spectrum antimicrobial therapies reduces mortality [9]. However, in the past few years, rising rates of treatment failure to such antimicrobial therapies caused the clinicians to see the alternative options to manage the current scenario.

In the present case patient was empirically put on meropenem and shifted to colistin, but did not responded to both the treatments. Blood culture sensitivity test confirmed the presence of KPC producing K. pneumoniae which was resistant to both colistin and meropenem antibiotics but sensitivity to Elores. According to the susceptibility result, only Elores antibiotics could be used in this case. Patient was switched to Elores and the laboratory parameters improved from day 2 and recovered within 10 days of post Elores therapy.

In this case, patient was having bilateral lesions in the lung. During development of sepsis, bacteria damage lung epithelium and enter the bloodstream, inducing systemic inflammatory responses (for example, increased vascular permeability, leukocyte-endothelial adhesion, and activation of complement and clotting pathways) [2].

Elores is a combination of ceftriaxone, sulbactam and disodium edetate, having high susceptibility to ESBL and MBL producing pathogens including pathogens expressing NDM-1, VIM-1, KPC-2, IMP-1 [10]. The reason for enhanced susceptibility of Elores is synergistic activity of ceftriaxone, disodium edetate and sulbactam. Disodium edetate chelates the divalent ions required for the activity of MBLs thus de-activating the MBLs which in turn enhanced the susceptibility of Elores towards MBLs producing organisms [11,12].

Elores showed significant susceptibility against ESBLs and MBLs producing K. pneumoniae clinical isolates. In a study done on K. pneumoniae isolated from North Indian patients, Elores MICswere reported between 4-8 μg/ml in KPC producing pathogens, the time kill-curve of Elores demonstrated long and effective bactericidal activity (5-log reductions in the viable cell counts in 12hours) [11]. Apart from invitro studies, in a phase-III clinical trail on Elores, high susceptibility to all isolates positive with ESBL and MBL genes were observed, including KPC-2 [13]. Similarly, a retrospective study on 95 patients with LRTI, UTI and IAI with various Gram negative infections showed increasing prevalence of carbapenem resistant, while Elores showed excellent antibacterial activity against major Gram negative organisms identified including Klebsiella species (84%). Elores also showed higher clinical success rate of more than 75% as compared to meropenem 61% [14]. Very recently, its efficacy has also been demonstrated in complicated neurogenic bladder and multiloculated left pleural effusion case [15,16].

Hence, in view of the risk of spreading of ESBLs and MBLs resistant determinants in fatal diseases like sepsis, it is important to develop a new antibiotic combination that could be effective against ESBLs and MBLs producing strains. Antibiotic adjuvants like Elores could be a useful strategy in the current scenario.

Sepsis is a systemic infection that can lead to multi-organ failure and death. With increasing incidence of MDR Gram-negative pathogens and rise in KPC producing K. pneumoniae has created a therapeutic challenge in treating sepsis patients and raised a need for an antibiotic with novel mechanism of actions to tackle the current scenario. The present case report highlights the safety and efficacy of Elores: an antibiotic adjuvant entity with synergistic mechanism of action in managing MDR pathogens and can be considered as a drug of choice for treating KPC.

[1]. Alexandraki I, Palacio C, Gram-negative versus Gram-positive bacteremia: what is more alarming Critical Care 2010 14(3):161  [Google Scholar]

[2]. Karabinis A, Paramythiotou E, Mylona-Petropoulou D, Kalogeromitros A, Katsarelis N, Kontopidou F, colistin for Klebsiella pneumoniae-associated sepsis Clinical Infectious Disease 2004 38(1):e7-9.  [Google Scholar]

[3]. Arnold RS, Thom KA, Sharma S, Philips M, Johnson JK, Morgan DJ, Emergence of Klebsiella pneumoniae carbapenemase (KPC)-producing bacteria South Medical Journal 2011 104(1):40-45.  [Google Scholar]

[4]. Sreedharan S, Faizal B, Manohar R, Pillai MGK, Patterns and complications of sepsis in critically ill patients and the role of APACHE IV score in predicting mortality Amrita Journal of Medicine 2012 8(1):19-23.  [Google Scholar]

[5]. Nasa P, Juneja D, Singh O, Dang R, Arora V, Severe sepsis and its impact on outcome in elderly and very elderly patients admitted in intensive care unit Journal of Intensive Care Medicine 2012 27(3):179-83.  [Google Scholar]

[6]. Gupta V, Bansal N, Singla N, Chander J, Occurrence and phenotypic detection of class A carbapenemases among Escherichia coli and Klebsiella pneumoniae blood isolates at a tertiary care center Journal of Microbiology, Immunology and Infection 2013 46(2):104-08.  [Google Scholar]

[7]. Chaudhary M, Payasi A, A new antibiotic adjuvant entity active against metallo- β-lactamases producing organisms International Journal of Medicine and Medical Sciences 2012 46(2):1145-50.  [Google Scholar]

[8]. Du X, Ying Fu, Yunsong Y, Tigecycline treatment of infection caused by KPC-producing Escherichia coli in a pediatric patient Annals of Clinical Microbiology and Antimicrobials 2013 12:19  [Google Scholar]

[9]. Bernhard M, Lichtenstern C, Eckmann C, Weigand MA, The early antibiotic therapy in septic patients-milestone or sticking point Critical Care 2014 18(6):671  [Google Scholar]

[10]. Chaudhary M, Payasi A, Molecular characterization and antimicrobial susceptibility study of Acinetobacter baumannii clinical isolates from Middle East, African and Indian patients Journal of Proteomics and Bioinformatics 2012 5(11):265-69.  [Google Scholar]

[11]. Chaudhary M, Payasi A, Antimicrobial susceptibility patterns and molecular characterization of Klebsiella pneumoniae clinical isolates from North Indian patients International Journal of Medicine and Medical Sciences 2013 46(2):1218-24.  [Google Scholar]

[12]. Chaudhary M, Payasi A, Rising antimicrobial resistance of Pseudomonas aeruginosa isolated from clinical specimens in India Journal of Proteomics and Bioinformatics 2013 6(1):05-09.  [Google Scholar]

[13]. Chaudhary M, Payasi A, A randomized, open-label, prospective, multicenter phase-III clinical trial of Elores in lower respiratory tract and urinary tract infections Journal of Pharmacy Research 2013 6:409-14.  [Google Scholar]

[14]. Bhatia P, Alternative empiric therapy to carbapenems in management of drug resistant Gram-negative pathogens: a new way to spare carbapenems Research Journal of Infectious Diseases 2015 3(2):1-9.  [Google Scholar]

[15]. Goyal S, Management of pneumonia with multiloculated left pleural effusion cased by extended spectrum beta-lactamases producing Klebsiella pneumoniae Internaltional Journal of Clinical and Biomedical Research 2015 1(4):73-6.  [Google Scholar]

[16]. Singh MK, Catheter associated multi drug resistant Klebsiella pneumoniae infection management with Elores in complicated neurogenic bladder case International Journal of Scientific Research 2015 4(10)  [Google Scholar]