|Year : 2014 | Volume
| Issue : 4 | Page : 453-455
Clinical study of carbapenem sensitive and resistant Gram-negative bacteremia in neutropenic and nonneutropenic patients: The first series from India
AK Ghafur, PR Vidyalakshmi, P Kannaian, R Balasubramaniam
Department of Infectious Diseases, Apollo Speciality Hospital, Chennai, Tamil Nadu, India
|Date of Web Publication||1-Feb-2016|
A K Ghafur
Department of Infectious Diseases, Apollo Speciality Hospital, Chennai, Tamil Nadu
Source of Support: None, Conflict of Interest: None
Objective: Carbapenem resistance is a growing global concern. There is a lack of published clinical studies on the topic from Indian subcontinent. Aim of this study was to analyze clinical profile of patients with carbapenem sensitive and resistant bacteremia among neutropenic and nonneutropenic patients. Materials And Methods: Retrospective analysis of 141 patients who had carbapenem resistant or sensitive Gram-negative bacteremia, identified over a period of 1-year was done by medical records review, in Apollo Specialty Hospital, a 300-bedded tertiary care Oncology, neurosurgical and orthopedic center in South India. Results: Of the total 141 patients with Gram-negative bacteremia, 44 had carbapenem resistant ones. Of these 44 patients, 17 were neutropenics (resistant neutropenic group) and 27 nonneutropenic patients (resistant nonneutropenic group). Of the 97 patients with carbapenem sensitive bacteremia, 43 were neutropenic (sensitive neutropenic group) and 54 nonneutropenics (sensitive nonneutropenic group). The 28 days mortality was significantly higher in carbapenem resistant bacteremic group compared to the sensitive one (P = 0.008). Conclusion: This is the first study from India comparing clinical features of patients with carbapenem sensitive and resistant blood stream infections. Patients with carbapenem resistant bacteremia had higher mortality compared to patients with sensitive bacteremia.
Keywords: Carbapenem resistant and carbapenem resistant Gram-negative bacteremia, clinical study, neutropenics, nonneutropenics India
|How to cite this article:|
Ghafur A K, Vidyalakshmi P R, Kannaian P, Balasubramaniam R. Clinical study of carbapenem sensitive and resistant Gram-negative bacteremia in neutropenic and nonneutropenic patients: The first series from India. Indian J Cancer 2014;51:453-5
|How to cite this URL:|
Ghafur A K, Vidyalakshmi P R, Kannaian P, Balasubramaniam R. Clinical study of carbapenem sensitive and resistant Gram-negative bacteremia in neutropenic and nonneutropenic patients: The first series from India. Indian J Cancer [serial online] 2014 [cited 2019 Jun 24];51:453-5. Available from: http://www.indianjcancer.com/text.asp?2014/51/4/453/175362
| » Introduction|| |
Carbapenem resistance is a growing global concern with highest rates reported from South Asia and Mediterranean countries., There are plenty of published reports from Mediterranean countries and other western countries, on the clinical profile of patients infected with carbapenem resistant bacteria, consistently reporting high morbidity and mortality.,,,,,,,,,,,,,,,, Treatment strategy for patients with carbapenem resistant Gram-negative bacterial (CRGNB) infections is a topic of ongoing debate; with unresolved conclusion whether colistin monotherapy or colistin based combination therapy is superior.,Klebsiella pneumoniae carbapenemase (KPC) is the predominant molecular mechanism of resistance in the west, while New Delhi Metallo-beta-lactamase (NDM) is the most common one in South Asia. It is unknown whether the strategy followed in KPC producing bacterial infections could be extrapolated to NDM type. Though there are plenty of publications on the in vitro characteristics of carbapenem resistant bacteria, lack of published data on clinical profile including morbidity, mortality and treatment options from Indian subcontinent; is a serious impediment, forcing clinicians to infer available data from the west, while making therapeutic decisions. Aim of this study was to analyze clinical profile of patients with carbapenem sensitive and resistant bacteremia among neutropenic and nonneutropenic patients.
| » Materials And Methods|| |
Retrospective analysis of 141 patients who had carbapenem resistant or sensitive Gram-negative bacteremia, identified over a period of 1-year was done by medical records review, in Apollo Specialty Hospital, a 300-bedded tertiary care Oncology, neurosurgical and orthopedic center in South India. Institutional ethics committee approval was obtained prior to analysis. Bacterial identification and susceptibility were done using VITEK2 compact system. The isolates were tested against piperacillin-tazobactam, gentamicin, amikacin, netilmycin, ceftazidime, cefoperazone-sulbactam, cefepime, cefepime/tazobactam, imipenem, meropenem, ciprofloxacin, trimethoprim/sulfamethoxazole andtigecycline. While clear-cut CLSI guidelines on breakpoints are available for Enterobacteriacea and Pseudomonas to most antibiotics; there is no defined breakpoint for cefoperazone-sulbactam and cefepime/tazobactam., Breakpoints of cefoperazone and cefepime were applied for cefoperazone/sulbactam and cefepime/tazobactam respectively. Antibiotic discs for these drugs were obtained from HI Media Lab India. Colistin susceptibility was done using VITEK 2 compact for all isolates and for some isolates minimum inhibitory concentration by E-test according to availability.
Hospital identification numbers of patients with Gram-negative bacteremia between January and December 2012 were recovered from microbiology laboratory, and their medical records were tracked and analyzed. Data for variables such as age, sex, underlying immunocompromising condition, co-morbidities, Intensive Care Unit (ICU) stay, presence of indwelling devices and prior antibiotic exposure were looked into. Pitt's bacteremia score and Charlsons comorbidity index were calculated for all patients. The outcome, including 28-day mortality was analyzed; however, attributable mortality was not calculated.
Antimicrobial therapy was considered appropriate if the treatment regimen included antibiotics that were active in vitro.
| » Results|| |
Of the total 141 patients with Gram-negative bacteremia, 44 had carbapenem resistant ones. Of these 44 patients, 17 were neutropenics (resistant neutropenic [RN] group) and 27 nonneutropenic patients (resistant nonneutropenic [RNN] group). Of the 97 patients with carbapenem sensitive bacteremia, 43 were neutropenic (sensitive neutropenic [SN] group) and 54 nonneutropenics (sensitive nonneutropenic [SNN] group). In RN group 6 had Klebsiella, 8 Pseudomonas and 3 Acinetobacter. SN group had 11 Klebsiella, 23 Escherichia coli, 7 Pseudomonas and 2 Acinetobacter isolates. RNN group had 11 Klebsiella, 4 E. coli, 10 Pseudomonas and 2 Acinetobacter compared to 11 Klebsiella, 33 E. coli, 8 Pseudomonas and 2 Acinetobacter among the SNN cases.
There was no statistically significant difference in the age among the study groups (Mean age RN 30.7, SN 39.9 P = 0.12; RNN 50.9, SNN 53.4, P = 0.54). Total leukocyte count on the day of bacteremia had no direct association with the prognosis in RN compared to SN (P = 0.96) and SNN compared RNN (P = 0.55). There was no statistically significant difference in the duration of ICU stay prior to development of bacteremia in RN compared to SN (mean ICU stay 3.4 and 2.02 days, P = 0.31), but there was a significant difference between RNN and SNN (10.4 and 3.63 days P = 0.002).
Of the 141 patients studied, 32 (22.6%) had prior Gram-negative bacteremia. Of the 44 CR patients, 17 (38.6%) had prior bacteremia, while only 15/97 (15.5%) in the CS group had a prior bacteremia (P = 0.002). Of the 32 patients with prior bacteremia, 13 (16%) were nonneutropenics and 19 (46.3%) were neutropenics (P = 0.029), indicating that prior bacteremia is a risk factor for development of carbapenem resistant bacteremia especially among neutropenics.
Twenty-eight days mortality among the carbapenem resistant bacteremia group, 28/44 (63.7%) was significantly higher than carbapenem sensitive group, 37/97 (38.2%) with a P = 0.008. In neutropenic carbapenem resistant group, though there was a high observedmortality (53%) while compared to SN, the difference was not statistically significant (P = 0.177). In carbapenem, RNN group mortality was significantly higher (70.4% RNN, 44.5% SNN; P = 0.04) compared to SNNs.
There was no significant difference in APACHEII score between RN group and SN group (P = 0.143), but there was a significant difference between RNN group and SNN group (P = 0.001). A similar trend was noted in Pitt's bacteremia score as well (0.495 and 0.021). As the sample size was small, we could not analyze the impact of various treatment strategies. However, in the carbapenem resistant bacteremia group, of the 26/44 who died, only 15 had received colistin.
| » Discussion|| |
Antibiotics revolutionized modern medicine. Carbapenems are the most potent weapons in our armory against Gram-negative bacterial infections. Increasing carbapenem resistance has literally compromised the performance of patients undergoing transplant, chemotherapy and intensive care, making them vulnerable to infections with limited therapeutic options., It is extremely important to study the clinical characteristics of these patients to understand risk factors for acquisition and transmission of carbapenem resistant bacteria and response to various treatment options, which will help us designing strategies to prevent the transmission and to achieve the best outcome. Lack of available good quality data from the region is a serious impediment in formulating preventive and therapeutic strategy. The first available data on the clinical spectrum of these patients was the conference abstract version of the current paper.
The most striking finding of the study is the significantly high mortality in patients with carbapenem resistant bacteremia compared to patients with carbapenem sensitive ones. It is a well-established fact that resistant bacteria are in general not more virulent than their sensitive counterparts. Half of the patients who died in the carbapenem resistant bacteremia group did not receive empirical colistin within 48 h of blood culture collection. Lack of administration of the right antibiotic at the right time is an important cause of high mortality in patients with sepsis. Unfortunately, the only right antibiotic in treating sepsis due to CRGNB infections is colistin, the last available weapon in our armamentarium. In view of increasing reports of colistin resistance from centers across the world, including our center, administering colistin to all patients with suspected sepsis will be impractical and will accentuate the dangerous scenario of colistin resistance. A right balance will be to identify the highest risk population and reserve empirical colistin usage to these patients. Our study confirms that neutropenic patients remaining febrile on broad-spectrum agents such as beta-lactam beta-lactamase inhibitors or carbapenems are eligible candidates to receive colistin at least for 48–72 h, until early culture results are available. Comparable disease severity scores (APACHE II and Pitt's bacteremia score) in carbapenem resistant and sensitive patients in the neutropenic group, is a strong argument for empirical colistin use in these patients, despite their apparent clinical stability. Though this practice may lead to over usage of colistin in neutropenic patients, strict antibiotic stewardship with colistin discontinuation after 48–72 h, if early culture results do not reveal a CRGNB, could be the ideal strategy in Indian oncology centers and centers in other regions with high carbapenem resistance. In the nonneutropenic patients, APACHE score was higher in carbapenem resistant bacteremia group. Colistin empirical therapy is not indicated for hemodynamically stable nonneutropenic patients.
The duration of ICU stay was longer in nonneutropenic carbapenem resistant bacteremia group, but there was no significant difference in neutropenics. This is not surprising considering the understanding that the most common source of bacteremia in a neutropenic patient is gut translocation as a result of mucositis where the already colonized resistant/sensitive bacteria gain entry to blood stream, irrespective of the duration of the ICU stay. In nonneutropenic population, however, longer duration of the ICU stay predisposes to carbapenem resistant bacteremia. Another explanation to this difference in neutropenics and nonneutropenics could be the rapid deterioration of the neutropenic patient while being in the oncology ward and the blood culture collected shortly after shifting to ICU, clarifying the short duration of ICU stay in neutropenics prior to the development of bacteremia. Prior bacteremia was a risk factor for the development of carbapenem resistant bacteremia especially among neutropenics. The study was not large enough to conclude whether colistin based combination therapy is better than monotherapy or not. An excellent meta-analysis by Paul et al. has aptly pointed out the inherent potential of small observational studies, to produce spurious conclusions, regarding the superiority of combination therapy over monotherapy.
| » Conclusion|| |
This is the first study from India comparing clinical features of patients with carbapenem sensitive and resistant blood stream infections. Mortality was higher in patients with carbapenem resistant bacteremia, compared to carbapenem sensitive bacteremia group. There is a definite role for empirical usage of colistin in high-risk febrile neutropenic patients, but not in hemodynamically stable nonneutropenic patients. The study was not powered enough to analyze impact of various treatment strategies. There is an urgent need for prospective studies.
| » References|| |
Ghafur A. Can India be the wing commander in the global fight against antimicrobial resistance? J Assoc Physicians India 2012;60:42-3.
Ghafur A. A Call to action: For the attention of oncologists! South Asian J Cancer 2012;1:48-9.
Borer A, Saidel-Odes L, Riesenberg K, Eskira S, Peled N, Nativ R, et al.
Attributable mortality rate for carbapenem-resistant Klebsiella pneumoniae
bacteremia. Infect Control Hosp Epidemiol 2009;30:972-6.
Routsi C, Pratikaki M, Platsouka E, Sotiropoulou C, Nanas S, Markaki V, et al
. Carbapenem-resistant versus carbapenem-susceptible Acinetobacter baumannii
bacteremia in a Greek intensive care unit: Risk factors, clinical features and outcomes. Infection 2010;38:173-80.
Ben-David D, Kordevani R, Keller N, Tal I, Marzel A, Gal-Mor O, et al.
Outcome of carbapenem resistant Klebsiella pneumoniae
bloodstream infections. Clin Microbiol Infect 2012;18:54-60.
Chang HJ, Hsu PC, Yang CC, Kuo AJ, Chia JH, Wu TL, et al.
Risk factors and outcomes of carbapenem-nonsusceptible Escherichia coli
bacteremia: A matched case-control study. J Microbiol Immunol Infect 2011;44:125-30.
Patel G, Huprikar S, Factor SH, Jenkins SG, Calfee DP. Outcomes of carbapenem-resistant Klebsiella pneumoniae
infection and the impact of antimicrobial and adjunctive therapies. Infect Control Hosp Epidemiol 2008;29:1099-106.
Alexander BT, Marschall J, Tibbetts RJ, Neuner EA, Dunne WM Jr, Ritchie DJ. Treatment and clinical outcomes of urinary tract infections caused by KPC-producing Enterobacteriaceae
in a retrospective cohort. Clin Ther 2012;34:1314-23.
Capone A, Giannella M, Fortini D, Giordano A, Meledandri M, Ballardini M, et al.
High rate of colistin resistance among patients with carbapenem-resistant Klebsiella pneumoniae
infection accounts for an excess of mortality. Clin Microbiol Infect 2013;19:E23-30.
Daikos GL, Petrikkos P, Psichogiou M, Kosmidis C, Vryonis E, Skoutelis A, et al.
Prospective observational study of the impact of VIM-1 metallo-beta-lactamase on the outcome of patients with Klebsiella pneumoniae
bloodstream infections. Antimicrob Agents Chemother 2009;53:1868-73.
Qureshi ZA, Paterson DL, Potoski BA, Kilayko MC, Sandovsky G, Sordillo E, et al.
Treatment outcome of bacteremia due to KPC-producing Klebsiella pneumoniae
: Superiority of combination antimicrobial regimens. Antimicrob Agents Chemother 2012;56:2108-13.
Rihani DS, Wallace MR, Sieger BE, Waite RA, Fox M, Brown SA, et al.
Over-treatment of carbapenemase-producing Enterobacteriaceae
. Scand J Infect Dis 2012;44:325-9.
Souli M, Kontopidou FV, Papadomichelakis E, Galani I, Armaganidis A, Giamarellou H. Clinical experience of serious infections caused by Enterobacteriaceae
producing VIM-1 metallo-beta-lactamase in a Greek University Hospital. Clin Infect Dis 2008;46:847-54.
Tumbarello M, Viale P, Viscoli C, Trecarichi EM, Tumietto F, Marchese A, et al.
Predictors of mortality in bloodstream infections caused by Klebsiella pneumoniae
carbapenemase-producing K. pneumoniae
: Importance of combination therapy. Clin Infect Dis 2012;55:943-50.
Lee GC, Burgess DS. Treatment of Klebsiella pneumoniae
carbapenemase (KPC) infections: A review of published case series and case reports. Ann Clin Microbiol Antimicrob 2012;11:32.
Kontopoulou K, Protonotariou E, Vasilakos K, Kriti M, Koteli A, Antoniadou E, et al.
Hospital outbreak caused by Klebsiella pneumoniae
producing KPC-2 beta-lactamase resistant to colistin. J Hosp Infect 2010;76:70-3.
Mammina C, Bonura C, Di Bernardo F, Aleo A, Fasciana T, Sodano C, et al.
Ongoing spread of colistin-resistant Klebsiella pneumoniae
in different wards of an acute general hospital, Italy, June to December 2011. Euro Surveill 2012;17:pii20248.
Marchaim D, Chopra T, Pogue JM, Perez F, Hujer AM, Rudin S, et al.
Outbreak of colistin-resistant, carbapenem-resistant Klebsiella pneumoniae
in metropolitan Detroit, Michigan. Antimicrob Agents Chemother 2011;55:593-9.
Valencia R, Arroyo LA, Conde M, Aldana JM, Torres MJ, Fernández-Cuenca F, et al.
Nosocomial outbreak of infection with pan-drug-resistant Acinetobacter baumannii
in a tertiary care university hospital. Infect Control Hosp Epidemiol 2009;30:257-63.
Falagas ME, Lourida P, Poulikakos P, Rafailidis PI, Tansarli GS. Antibiotic treatment of infections due to carbapenem-resistant Enterobacteriaceae
: Systematic evaluation of the available evidence. Antimicrob Agents Chemother 2014;58:654-63.
Paul M, Carmeli Y, Durante-Mangoni E, Mouton JW, Tacconelli E, Theuretzbacher U, et al
. Combination therapy for carbapenem-resistant Gram-negative bacteria. J Antimicrob Chemother 2014;69:2305-9.
Pereira V, Lopes C, Castro A, Silva J, Gibbs P, Teixeira P. Characterization for enterotoxin production, virulence factors, and antibiotic susceptibility of Staphylococcus aureus
isolates from various foods in Portugal. Food Microbiol 2009;26:278-82.
Mouton JW, Melchers R, Mil AV.In Vitro
Activity of Cefepime Alone and in Combination with Tazobactam against ESBL Producers. Boston, USA: Poster Session Presented at ICAAC; 2010. p. A-2251.
Abdul Ghafur K. An obituary – On the death of antibiotics! J Assoc Physicians India 2010;58:143-4.
Arias CA, Murray BE. Antibiotic-resistant bugs in the 21st
century – A clinical super-challenge. N Engl J Med 2009;360:439-43.
Ghafur A, Kannaian P, Tayade A. Clinical Study on Carbapenem Sensitive and Carbapenem Resistant Bacteremia in Neutropenic and Non-Neutropenic Patients – TheFirst Series From India. Berlin: ECCMID; 2013. p. 1368.
Ghafur A, Vidyalakshmi PR, Priyadarshini K, Thirunarayanan MA. An Obituary to Antibiotics – Emergence of Pan Drug Resistance amongst Gram Negative Bacteria. CIDSCON; 2013.