- Email: [email protected]
blaOXA-48 carrying clonal colistin resistant-carbapenem resistant Klebsiella pneumoniae in neonate intensive care unit, India
Microbial Pathogenesis 100 (2016) 75e77
Contents lists available at ScienceDirect
Microbial Pathogenesis journal homepage: www.elsevier.com/locate/micpath
blaOXA-48 carrying clonal colistin resistant-carbapenem resistant Klebsiella pneumoniae in neonate intensive care unit, India Santosh Kumar Singh a, Minakshi Gupta b, * a b
School of Biological Sciences, National Institute of Science Education and Research, Jatni, Odisha, India TATA Main Hospital, Jamshedpur, Jharkhand, India
a r t i c l e i n f o
a b s t r a c t
Article history: Received 4 August 2016 Received in revised form 7 September 2016 Accepted 9 September 2016 Available online 10 September 2016
Bacteria resistant to colistin, a last resort antibiotic reflect the pre-antibiotic era. In this study, colistin resistance carbapenem-resistant K. pneumoniae (COLR- CRKP) strains from neonate's intensive care unit were evaluated. Molecular analysis showed that all the four colistin resistant K. pneumoniae isolates were clonally related with strong biofilm formation ability and harbored blaSHV-34 and blaOXA-48 genes. Our result suggested the need of proper surveillance and adequate infection control to limiting the spread of these organisms. © 2016 Elsevier Ltd. All rights reserved.
Keywords: Klebsiella pneumoniae Colistin resistance Pandrug resistant
Neonatal sepsis is a clinical condition of blood stream infection (BSI) characterized by systemic signs and symptoms in the new born baby of 1e28 days. In India, National Neonatal Perinatal Database showed that the incidence of neonatal sepsis was 30 per 1000 live births which is more in the rural areas (49e170 per1000 live births), contributing upto 40% of all neonatal deaths [1,2]. Klebsiella pneumoniae is the most commonly implicated pathogen responsible for neonatal sepsis [3]. Recently, multidrug resistant (MDR) K. pneumoniae outbreaks in neonatal intensive care unit (NICU) had been reported from developing and developed countries [4e8]. The hydrolysis of b-lactam ring mediated by b-lactamases made b-lactam antibiotics ineffective. Extended spectrum blactamase (ESBL) producing K. pneumoniae strains were responsible for 97% bloodstream infections in neonatal and pediatric intensive care units in India with high morbidity and mortality [9]. Further, metallo-b-lactamase and carbapenemase producing K. pneumoniae strains make the clinical management of these infections more challenging. In 2013, carbapenem resistant K. pneumoniae (CRKP) was tagged as urgent threat by the Centers for Disease Control and Prevention (CDC). Irrespective of the nephrotoxicity and ototoxicity risk, colistin was frequently used as a last resort antibiotic to treat carbapenem resistant K. pneumoniae [10], lead recently resistance to this drug. In this study, we reported the occurrence of clonal
* Corresponding author. E-mail address: [email protected] (M. Gupta). http://dx.doi.org/10.1016/j.micpath.2016.09.009 0882-4010/© 2016 Elsevier Ltd. All rights reserved.
colistin resistant carbapenem resistant K. pneumoniae (COLR- CRKP) bacteremia in the neonate intensive care unit of a secondary care hospital, India. Isolates KPC 142 and KPC 143 were isolated from twin females on 13th March 2016, whereas isolates KPC 144 and KPC 145 were isolated from two individual male children on 14th and 22nd March 2016 respectively. The clinical characteristic, demographic, biochemical data, outcomes of patients were assessed from patients records (Table 1). Identification and antibiotic susceptibility of organisms were done by VITEK® 2 compact system (bioMerieux, USA) using the ID-GNB and AST-N280 cards in accordance with the manufacturer's instructions. Colistin resistance of the isolates were confirmed by disc diffusion method and broth-double dilution method and interpreted according to the EUCAST breakpoints (11 mm zone of inhibition and 4 mg/l MIC as resistant). Phenotypic detection of ESBLs, MBLs and carbapenemase of COLRCRKP were carried out by double disk synergic test, imipenem EDTA double disc synergy test and Modified Hodge test (MHT) respectively following the protocol as described in CLSI 2014 manual. Genotypic detection of b-lactamases were determined sequentially by PCR and confirmed by restriction digestion. Primers, annealing temperature and product size were given in Table S2. Biofilm formation was detected by 0.1% crystal violet method as described by Stepanovic et al., 2000 [11]. The clonal profile of the COLR-CRKP isolates were investigated by ERIC-PCR using primer set ERIC-2/ERIC-1026 according to Munoz et al., 2007 [12] and compared with COLS-CRKP isolated from same NICU
76
S.K. Singh, M. Gupta / Microbial Pathogenesis 100 (2016) 75e77
Table 1 Clinical and biochemical details of patients having Klebsiella pneumoniae bacteremia. Patients
P1 P2 P3 P4
Age/Gender
2 2 8 6
days/F days/F days/M days/M
Reason for admission
Low Birth Weight Low Birth Weight Birth Asphyxia Meconium stained liquor
Hb (gm/dl)
TLC (per mm3)
Platelet (per mm3)
CRP (mg/dl)
0 day
5days
0 day
5days
0 day
5days
0 day
5days
21.8 19.5 14.4 15.9
15.5 13.6 13.3 13
9400 13700 11000 9100
1700 5600 27700 5100
208000 235000 238000 219000
24000 14000 32000 18000
0.05 0.28 0.11 0.01
3.2 e e 4.91
Days in NICU
Status when discharged
20 days 15 days 10 days 8 days
Alive Dead Alive Alive
Hb- Hemoglobin; TLC- Total leukocyte count; CRP- C reactive protein.
Table 2 Minimum inhibitory concentration (mg/L) and b-lactamase of isolated Klebsiella pneumoniae from neonates. Isolates
KPC-142 KPC-143 KPC-144 KPC-145
Date of isolation
13/03/2016 13/03/2016 14/03/2016 22/03/2016
b-lactamase
MIC (mg/l) of antibiotics AMC
TZP
CXM
CRO
CPM
CSS
ERT
IPM
MEM
AMK
GEN
NAL
CIP
TGC
CST
SXT
32 32 32 32
128 128 128 128
64 64 64 64
1 1 1 1
1 1 1 1
64 64 64 64
8 8 8 8
2 2 2 2
16 16 16 16
64 64 64 64
16 16 16 16
32 32 32 32
4 4 4 4
2 2 2 2
16 16 16 16
20 20 20 20
blaSHV-34, blaSHV-34, blaSHV-34, blaSHV-34,
blaOXA-48 blaOXA-48 blaOXA-48 blaOXA-48
AMC- amoxicillin/clavulanic acid, TZP- piperacillin/tazobactam, CXM-cefuroxime, CRO-ceftriaxone, CPM-cefepime, CSS-cefoperazone/sulbactam, IPM-imipenem, MEMmeropenem, AMK-amikacin, Gen-gentamicin, NAL-nalidixic acid, CIP-ciprofloxacin, TGC-tigecycline, CST- colistin, SXT- trimethoprim/sulphamethoxazole
Figure 1. Dendrogram of colistin susceptible-carbapenem-resistant (COLS- CRKP) and colistin resistant-carbapenem-resistant Klebsiella pneumoniae (COLR- CRKP) isolates based on ERIC PCR. The dendrogram was constructed on the basis of the averaged similarity of the matrix with the use of the algorithm of the Unweighted Pair-Group Method (UPGMA) using PyElph software.
in 2014. As shown in Table 2, all the four COLR- CRKP isolates exhibited resistance towards b-lactams as well as b-lactam/b-lactamase inhibitor combination, quinolones, aminoglycosides and colistin whereas susceptible to tigecycline and co-trimoxazole. These isolates displayed much lower MICs to ceftriaxone, cefepime and imipenem, compared to colistin-susceptible carbapenem-resistant K. pneumoniae isolated in 2014 in the same hospital (Table S1). Double disk synergy test and imipenem EDTA double disc synergy test were negative all four COLR- CRKP isolates but exhibited positive MHT (Figure S1a). Extended spectrum b-lactamase gene (blaSHV-34) and carbapenemase gene (blaOXA-48) were detected in all the four COLR- CRKP isolates using PCR method (Figure S1b/ Table 2). Biofilm limits the effectiveness of many antibiotics due to extracellular polymeric barrier. All the four COLR- CRKP isolates
were strong biofilm former (Fig. S2). Using ERIC-PCR, COLR- CRKP isolates appeared as a single clone distinct from COLS-CRKP isolated in 2014 as shown in Fig. 1. Antibiotic resistance is an inevitable phenomenon associated with antibiotic usage and microbial evolution [13]. In 2010 analysis, India was the largest consumer of different classes of antibiotic (12$9 109 units, 10$7 units per person) with 23% increase in the retail sales [14]. An increase of 29% carbapenem resistant K. pneumoniae infection in 2008e2014 prompted the use of colistin to treat this organism (www.resistancemap.org). With selection pressure from excessive use of colistin, increased resistance to this drug from 1% in 2013 to 3% in 2014 was reported (www. resistancemap.org). We present the first clonal K. pneumoniae isolates from NICU resistant to colistin. All strains had MICs 16 mg/L, clearly resistant by all known breakpoints. The four COLR- CRKP
S.K. Singh, M. Gupta / Microbial Pathogenesis 100 (2016) 75e77
K. pneumoniae isolates in the present studies considered to be pandrug resistant (PDR) as these isolates were susceptible to only tigecycline and co-trimoxazole. These two antibiotics can't be used for neonates as FDA has not been approved tigecycline for the treatment of bloodstream infections due to their low blood concentrations and SMX-TMP has ability to displace bilirubin from its binding sites on serum albumin [15,16]. Mortality attributed to infection from COLR- CRKP K. pneumoniae was recorded in one patient (25%). Prolonged or inadequate use of colistin leads to the emergence of colistin resistance leaving few or no treatment choices, increasing morbidity and mortality. This urges for the prudent use of antibiotics as it can avert the impending danger of losing out on the available antibiotics. Disclaimer statements
[3]
[4]
[5]
[6]
[7]
MG: Clinical studies, data acquisition, manuscript review and manuscript editing. SKS: concepts, molecular study design, literature search, data analysis and manuscript preparation.
[8]
Funding
[9]
This study was supported by the TATA Main Hospital, Jamshedpur, Jharkhand, India.
[10]
Conflicts of interest
[11]
None. Appendix A. Supplementary data
[12]
[13]
Supplementary data related to this article can be found at http:// dx.doi.org/10.1016/j.micpath.2016.09.009.
[14]
References
[15]
[1] National Neonatology Forum NNPD Network, National Neonatal-perinatal Database, National Neonatology Forum NNPD Network, New Delhi, 2005. Report for 2002-2003. [2] D. Thaver, A.K. Zaidi, Burden of neonatal infections in developing countries: a
[16]
77
review of evidence from community-based studies, Pediatr. Infect. Dis. J. 28 (1 Suppl) (2009 Jan) S3eS9, http://dx.doi.org/10.1097/INF.0b013e3181958755. R. Viswanathan, A.K. Singh, C. Ghosh, S. Dasgupta, S. Mukherjee, S. Basu, Profile of neonatal septicaemia at a district-level sick newborn care unit, J. Health Popul. Nutr. 30 (1) (2012 Mar) 41e48. Y. Jin, C. Shao, J. Li, H.1 Fan, Y. Bai, Y. Wang, Outbreak of multidrug resistant NDM-1-producing Klebsiella pneumoniae from a neonatal unit in Shandong Province, China, PLoS One 10 (3) (2015 Mar 23) e0119571, http://dx.doi.org/ 10.1371/journal.pone.0119571 eCollection 2015. J. Gray, W. Arvelo, J. McCracken, B. Lopez, F.C. Lessa, B. Kitchel, B. Wong, L. Reyes, K. Lindblade, An outbreak of Klebsiella pneumoniae late-onset sepsis in a neonatal intensive care unit in Guatemala, Am. J. Infect. Control 40 (6) (2012 Aug) 516e520, http://dx.doi.org/10.1016/j.ajic.2012.02.031. rez, N.M. Olarte Escobar, B. Castro-Cardozo, I.A. Valderrama J.A. Escobar Pe rquez, M.I. Garzo n Aguilar, L. Martinez de la Barrera, E.R. Barrero Barreto, Ma n, N. Vanegas Go mez, Outbreak of R.A. Marquez-Ortiz, M.V. Moncada Guayaza NDM-1-producing Klebsiella pneumoniae in a neonatal unit in Colombia, Antimicrob. Agents Chemother. 57 (4) (2013 Apr) 1957e1960, http:// dx.doi.org/10.1128/AAC.01447-12. S. Datta, S. Mitra, R. Viswanathan, A. Saha, S. Basu, Characterization of novel plasmid-mediated b-lactamases (SHV-167 and ACT-16) associated with New Delhi metallo-b-lactamase-1 harbouring isolates from neonates in India, J. Med. Microbiol. 63 (Pt 3) (2014 Mar) 480e482, http://dx.doi.org/10.1099/ jmm.0.067223-0. S. Roy, R. Viswanathan, A.K. Singh, P. Das, S. Basu, Sepsis in neonates due to imipenem-resistant Klebsiella pneumoniae producing NDM-1 in India, J. Antimicrob. Chemother. 66 (6) (2011 Jun) 1411e1413, http://dx.doi.org/ 10.1093/jac/dkr068. R.M. Parveen, M.A. Khan, G.A. Menezes, B.N. Harish, S.C. Parija, J.P. Hays, Extended-spectrum b-lactamase producing Klebsiella pneumoniae from blood cultures in Puducherry, India, Indian J. Med. Res. 134 (2011) 392e395. A.Y. Peleg, D.C. Hooper, Hospital-acquired infections due to gram-negative bacteria, N. Engl. J. Med. 362 (2010) 1804e1813, http://dx.doi.org/10.1056/ NEJMra0904124. S. Stepanovic, D. Vukovic, I. Dakic, B. Savic, M. Svabic-Vlahovic, A modified microtiter-plate test for quantification of Staphylococcal biofilm formation, J. Microbiol. Methods 40 (2000) 175e179. M.A. Munoz, F.L. Welcome, Y.H. Schukken, R.N. Zadoks, Molecular epidemiology of two Klebsiella pneumoniae mastitis outbreaks on a dairy farm in New York State, J. Clin. Microbiol. 45 (12) (2007 Dec) 3964e3971. G.H. Talbot, J. Bradley, J.E. Edwards, et al., Bad bugs need drugs: an update on the development pipeline from the antimicrobial availability task force of the infectious diseases society of America, Clin. Infect. Dis. 42 (2006) 657e668. T.P. Van Boeckel, S. Gandra, A. Ashok, Q. Caudron, B.T. Grenfell, S.A. Levin, R. Laxminarayan, Global antibiotic consumption 2000 to 2010: an analysis of national pharmaceutical sales data, Lancet Infect. Dis. 14 (8) (2014) 742e750. A.J. Brink, D. Bizos, K.D. Boffard, C. Feldman, D.C. Grolman, J. Pretorius, G.A. Richards, E. Steyn, Guideline summary: appropriate use of tigecycline, S Afr. J. Surg. 50 (1) (2012 Feb 14) 20e21. S.J. Wadsworth, B. Suh, In vitro displacement of bilirubin by antibiotics and 2hydroxybenzoylglycine in newborns, Antimicrob. Agents Chemother. 32 (10) (1988 Oct) 1571e1575.
Contents lists available at ScienceDirect
Microbial Pathogenesis journal homepage: www.elsevier.com/locate/micpath
blaOXA-48 carrying clonal colistin resistant-carbapenem resistant Klebsiella pneumoniae in neonate intensive care unit, India Santosh Kumar Singh a, Minakshi Gupta b, * a b
School of Biological Sciences, National Institute of Science Education and Research, Jatni, Odisha, India TATA Main Hospital, Jamshedpur, Jharkhand, India
a r t i c l e i n f o
a b s t r a c t
Article history: Received 4 August 2016 Received in revised form 7 September 2016 Accepted 9 September 2016 Available online 10 September 2016
Bacteria resistant to colistin, a last resort antibiotic reflect the pre-antibiotic era. In this study, colistin resistance carbapenem-resistant K. pneumoniae (COLR- CRKP) strains from neonate's intensive care unit were evaluated. Molecular analysis showed that all the four colistin resistant K. pneumoniae isolates were clonally related with strong biofilm formation ability and harbored blaSHV-34 and blaOXA-48 genes. Our result suggested the need of proper surveillance and adequate infection control to limiting the spread of these organisms. © 2016 Elsevier Ltd. All rights reserved.
Keywords: Klebsiella pneumoniae Colistin resistance Pandrug resistant
Neonatal sepsis is a clinical condition of blood stream infection (BSI) characterized by systemic signs and symptoms in the new born baby of 1e28 days. In India, National Neonatal Perinatal Database showed that the incidence of neonatal sepsis was 30 per 1000 live births which is more in the rural areas (49e170 per1000 live births), contributing upto 40% of all neonatal deaths [1,2]. Klebsiella pneumoniae is the most commonly implicated pathogen responsible for neonatal sepsis [3]. Recently, multidrug resistant (MDR) K. pneumoniae outbreaks in neonatal intensive care unit (NICU) had been reported from developing and developed countries [4e8]. The hydrolysis of b-lactam ring mediated by b-lactamases made b-lactam antibiotics ineffective. Extended spectrum blactamase (ESBL) producing K. pneumoniae strains were responsible for 97% bloodstream infections in neonatal and pediatric intensive care units in India with high morbidity and mortality [9]. Further, metallo-b-lactamase and carbapenemase producing K. pneumoniae strains make the clinical management of these infections more challenging. In 2013, carbapenem resistant K. pneumoniae (CRKP) was tagged as urgent threat by the Centers for Disease Control and Prevention (CDC). Irrespective of the nephrotoxicity and ototoxicity risk, colistin was frequently used as a last resort antibiotic to treat carbapenem resistant K. pneumoniae [10], lead recently resistance to this drug. In this study, we reported the occurrence of clonal
* Corresponding author. E-mail address: [email protected] (M. Gupta). http://dx.doi.org/10.1016/j.micpath.2016.09.009 0882-4010/© 2016 Elsevier Ltd. All rights reserved.
colistin resistant carbapenem resistant K. pneumoniae (COLR- CRKP) bacteremia in the neonate intensive care unit of a secondary care hospital, India. Isolates KPC 142 and KPC 143 were isolated from twin females on 13th March 2016, whereas isolates KPC 144 and KPC 145 were isolated from two individual male children on 14th and 22nd March 2016 respectively. The clinical characteristic, demographic, biochemical data, outcomes of patients were assessed from patients records (Table 1). Identification and antibiotic susceptibility of organisms were done by VITEK® 2 compact system (bioMerieux, USA) using the ID-GNB and AST-N280 cards in accordance with the manufacturer's instructions. Colistin resistance of the isolates were confirmed by disc diffusion method and broth-double dilution method and interpreted according to the EUCAST breakpoints (11 mm zone of inhibition and 4 mg/l MIC as resistant). Phenotypic detection of ESBLs, MBLs and carbapenemase of COLRCRKP were carried out by double disk synergic test, imipenem EDTA double disc synergy test and Modified Hodge test (MHT) respectively following the protocol as described in CLSI 2014 manual. Genotypic detection of b-lactamases were determined sequentially by PCR and confirmed by restriction digestion. Primers, annealing temperature and product size were given in Table S2. Biofilm formation was detected by 0.1% crystal violet method as described by Stepanovic et al., 2000 [11]. The clonal profile of the COLR-CRKP isolates were investigated by ERIC-PCR using primer set ERIC-2/ERIC-1026 according to Munoz et al., 2007 [12] and compared with COLS-CRKP isolated from same NICU
76
S.K. Singh, M. Gupta / Microbial Pathogenesis 100 (2016) 75e77
Table 1 Clinical and biochemical details of patients having Klebsiella pneumoniae bacteremia. Patients
P1 P2 P3 P4
Age/Gender
2 2 8 6
days/F days/F days/M days/M
Reason for admission
Low Birth Weight Low Birth Weight Birth Asphyxia Meconium stained liquor
Hb (gm/dl)
TLC (per mm3)
Platelet (per mm3)
CRP (mg/dl)
0 day
5days
0 day
5days
0 day
5days
0 day
5days
21.8 19.5 14.4 15.9
15.5 13.6 13.3 13
9400 13700 11000 9100
1700 5600 27700 5100
208000 235000 238000 219000
24000 14000 32000 18000
0.05 0.28 0.11 0.01
3.2 e e 4.91
Days in NICU
Status when discharged
20 days 15 days 10 days 8 days
Alive Dead Alive Alive
Hb- Hemoglobin; TLC- Total leukocyte count; CRP- C reactive protein.
Table 2 Minimum inhibitory concentration (mg/L) and b-lactamase of isolated Klebsiella pneumoniae from neonates. Isolates
KPC-142 KPC-143 KPC-144 KPC-145
Date of isolation
13/03/2016 13/03/2016 14/03/2016 22/03/2016
b-lactamase
MIC (mg/l) of antibiotics AMC
TZP
CXM
CRO
CPM
CSS
ERT
IPM
MEM
AMK
GEN
NAL
CIP
TGC
CST
SXT
32 32 32 32
128 128 128 128
64 64 64 64
1 1 1 1
1 1 1 1
64 64 64 64
8 8 8 8
2 2 2 2
16 16 16 16
64 64 64 64
16 16 16 16
32 32 32 32
4 4 4 4
2 2 2 2
16 16 16 16
20 20 20 20
blaSHV-34, blaSHV-34, blaSHV-34, blaSHV-34,
blaOXA-48 blaOXA-48 blaOXA-48 blaOXA-48
AMC- amoxicillin/clavulanic acid, TZP- piperacillin/tazobactam, CXM-cefuroxime, CRO-ceftriaxone, CPM-cefepime, CSS-cefoperazone/sulbactam, IPM-imipenem, MEMmeropenem, AMK-amikacin, Gen-gentamicin, NAL-nalidixic acid, CIP-ciprofloxacin, TGC-tigecycline, CST- colistin, SXT- trimethoprim/sulphamethoxazole
Figure 1. Dendrogram of colistin susceptible-carbapenem-resistant (COLS- CRKP) and colistin resistant-carbapenem-resistant Klebsiella pneumoniae (COLR- CRKP) isolates based on ERIC PCR. The dendrogram was constructed on the basis of the averaged similarity of the matrix with the use of the algorithm of the Unweighted Pair-Group Method (UPGMA) using PyElph software.
in 2014. As shown in Table 2, all the four COLR- CRKP isolates exhibited resistance towards b-lactams as well as b-lactam/b-lactamase inhibitor combination, quinolones, aminoglycosides and colistin whereas susceptible to tigecycline and co-trimoxazole. These isolates displayed much lower MICs to ceftriaxone, cefepime and imipenem, compared to colistin-susceptible carbapenem-resistant K. pneumoniae isolated in 2014 in the same hospital (Table S1). Double disk synergy test and imipenem EDTA double disc synergy test were negative all four COLR- CRKP isolates but exhibited positive MHT (Figure S1a). Extended spectrum b-lactamase gene (blaSHV-34) and carbapenemase gene (blaOXA-48) were detected in all the four COLR- CRKP isolates using PCR method (Figure S1b/ Table 2). Biofilm limits the effectiveness of many antibiotics due to extracellular polymeric barrier. All the four COLR- CRKP isolates
were strong biofilm former (Fig. S2). Using ERIC-PCR, COLR- CRKP isolates appeared as a single clone distinct from COLS-CRKP isolated in 2014 as shown in Fig. 1. Antibiotic resistance is an inevitable phenomenon associated with antibiotic usage and microbial evolution [13]. In 2010 analysis, India was the largest consumer of different classes of antibiotic (12$9 109 units, 10$7 units per person) with 23% increase in the retail sales [14]. An increase of 29% carbapenem resistant K. pneumoniae infection in 2008e2014 prompted the use of colistin to treat this organism (www.resistancemap.org). With selection pressure from excessive use of colistin, increased resistance to this drug from 1% in 2013 to 3% in 2014 was reported (www. resistancemap.org). We present the first clonal K. pneumoniae isolates from NICU resistant to colistin. All strains had MICs 16 mg/L, clearly resistant by all known breakpoints. The four COLR- CRKP
S.K. Singh, M. Gupta / Microbial Pathogenesis 100 (2016) 75e77
K. pneumoniae isolates in the present studies considered to be pandrug resistant (PDR) as these isolates were susceptible to only tigecycline and co-trimoxazole. These two antibiotics can't be used for neonates as FDA has not been approved tigecycline for the treatment of bloodstream infections due to their low blood concentrations and SMX-TMP has ability to displace bilirubin from its binding sites on serum albumin [15,16]. Mortality attributed to infection from COLR- CRKP K. pneumoniae was recorded in one patient (25%). Prolonged or inadequate use of colistin leads to the emergence of colistin resistance leaving few or no treatment choices, increasing morbidity and mortality. This urges for the prudent use of antibiotics as it can avert the impending danger of losing out on the available antibiotics. Disclaimer statements
[3]
[4]
[5]
[6]
[7]
MG: Clinical studies, data acquisition, manuscript review and manuscript editing. SKS: concepts, molecular study design, literature search, data analysis and manuscript preparation.
[8]
Funding
[9]
This study was supported by the TATA Main Hospital, Jamshedpur, Jharkhand, India.
[10]
Conflicts of interest
[11]
None. Appendix A. Supplementary data
[12]
[13]
Supplementary data related to this article can be found at http:// dx.doi.org/10.1016/j.micpath.2016.09.009.
[14]
References
[15]
[1] National Neonatology Forum NNPD Network, National Neonatal-perinatal Database, National Neonatology Forum NNPD Network, New Delhi, 2005. Report for 2002-2003. [2] D. Thaver, A.K. Zaidi, Burden of neonatal infections in developing countries: a
[16]
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