|Year : 2018 | Volume
| Issue : 1 | Page : 54-60
Molecular characterisation for clonality and transmission dynamics of an outbreak of Klebsiella pneumoniae amongst neonates in a tertiary care centre in South India
Chaitra Shankar1, Manish Kumar2, Ashtawarthani Baskaran1, Miracle Magdelene Paul1, Nithya Ponmudi2, Sridhar Santhanam2, Joy Sarojini Michael1, Balaji Veeraraghavan1
1 Department of Clinical Microbiology, Christian Medical College, Vellore, Tamil Nadu, India
2 Department of Neonatology, Christian Medical College, Vellore, Tamil Nadu, India
|Date of Web Publication||2-May-2018|
Dr. Manish Kumar
Department of Neonatology, Christian Medical College, Vellore - 632004, Tamil Nadu
Source of Support: None, Conflict of Interest: None
Purpose: Sepsis is a significant cause of morbidity and mortality amongst neonates. Klebsiella pneumoniae is a common cause of nosocomial outbreaks causing bacteraemia and having potential of acquiring plasmids enhancing antimicrobial resistance. In the present study, we investigate K. pneumoniae outbreak causing bacteraemia amongst neonates over a span of 2 months. Isolates were characterised for antimicrobial resistance, virulence, molecular typing for clonality and plasmid typing for transmission dynamics, and patient outcome was investigated. Methods: Thirteen isolates of K. pneumoniae were obtained during October–November 2016. Antimicrobial susceptibility testing was performed, and multiplex polymerase chain reaction (PCR) for β-lactamases and PCR for ompK35 and ompK36 were performed. To study hypervirulence, string test and PCR for rmpA and rmpA2 were performed. Multilocus sequence typing and Inc plasmid typing were carried out to study transmission dynamics. Results: Amongst 13 isolates, all isolates harboured blaSHVand blaTEM; 12 isolates carried blaCTX-M-1. ompK35 was present in all, but ompK36 was absent in 12 isolates. Ten isolates belonged to ST48, 6 amongst which contained IncFII (K) plasmid. One isolate each belonged to ST29, ST111 and ST2647 (novel clone). None of the isolates was hypervirulent. Conclusion: Extended-spectrum β-lactamase K. pneumoniae is commonly seen in Indian hospitals and main mechanisms being production of SHV, TEM and CTX-M enzymes as seen in the present study. Outer membrane porins contribute significantly to antimicrobial resistance. Emergence of new clones such as ST2647 implies continuous evolution of the organism and also potential for rapid genetic recombination leading to multidrug resistance. Outbreaks amongst neonates lead to fatal outcome, and stringent hospital infection control is necessary.
Keywords: Bacteraemia, extended-spectrum β-lactamases, Klebsiella pneumoniae, neonates, outbreak, ST48
|How to cite this article:|
Shankar C, Kumar M, Baskaran A, Paul MM, Ponmudi N, Santhanam S, Michael JS, Veeraraghavan B. Molecular characterisation for clonality and transmission dynamics of an outbreak of Klebsiella pneumoniae amongst neonates in a tertiary care centre in South India. Indian J Med Microbiol 2018;36:54-60
|How to cite this URL:|
Shankar C, Kumar M, Baskaran A, Paul MM, Ponmudi N, Santhanam S, Michael JS, Veeraraghavan B. Molecular characterisation for clonality and transmission dynamics of an outbreak of Klebsiella pneumoniae amongst neonates in a tertiary care centre in South India. Indian J Med Microbiol [serial online] 2018 [cited 2018 Sep 21];36:54-60. Available from: http://www.ijmm.org/text.asp?2018/36/1/54/231677
| ~ Introduction|| |
Sepsis is one of the significant factors contributing to morbidity and mortality amongst neonates. Neonatal sepsis can be classified as early-and late-onset sepsis. The most common causes of neonatal sepsis are Streptococcus agalactiae and Escherichia coli followed by other Gram-negative bacilli. These pathogens can be acquired from maternal flora, in utero infection or from the hospital environment. There can be infant and maternal risk factors for acquisition of the pathogens.
Klebsiella pneumoniae is a frequent cause of nosocomial infections such as urinary tract infections, pneumonia and bacteraemia. It is an established pathogen causing outbreaks in hospitals amongst adults and neonates posing a challenge to treatment due to acquired multidrug resistance and virulence factors.,, The increased incidence of hypermucoviscous/hypervirulent strains further complicates the microbiological cure of K. pneumoniae infections. There have been several reports of outbreaks in Neonatal Intensive Care Units (NICU) due to K. pneumoniae from various regions of the world including India.,,, Plasmids play a very important role in transmission dynamics of antimicrobial resistance. There is limited literature on the role of plasmids in K. pneumoniae outbreaks in nosocomial setting. The study of clonality of the isolates during an outbreak helps in understanding the source and also curbs further spread.
In the present study, we investigate a K. pneumoniae outbreak amongst neonates over a span of 2 months. The isolates were characterised for antimicrobial resistance, virulence, molecular typing for clonality and plasmid typing for transmission dynamics, and the outcome in neonates was investigated.
| ~ Methods|| |
Thirteen K. pneumoniae isolated from blood cultures of neonates during October–November 2016 at the Department of Clinical Microbiology, Christian Medical College, Vellore. The first positive blood culture from each patient was included in the study.
K. pneumoniae isolates from blood culture were identified by standard biochemical methods. Antimicrobial susceptibility testing for different classes of antimicrobials such as cephalosporins – ceftriaxone (30 μg), ceftazidime (30 μg), cefpodoxime (10 μg) and cefepime (30 μg); β-lactam/β-lactamase inhibitors – piperacillin/tazobactam (100/10 μg); carbapenems – imipenem (10 μg) and meropenem (10 μg); fluoroquinolones – ciprofloxacin (5 μg) and levofloxacin (5 μg), aminoglycosides – amikacin (30 μg), gentamicin (10 μg) and netilmicin (30 μg); tetracycline-minocycline (30 μg); glycylcycline-tigecycline (15 μg) and phenicol-chloramphenicol (30 μg) was performed for all the isolates by Kirby-Bauer disk diffusion method as recommended by Clinical Laboratory Standards Institute (CLSI) and interpreted according to CLSI 2016 guidelines.E. coli ATCC25922 and P. aeruginosa ATCC 27853 were used as control strains for susceptibility testing. Susceptibility to tigecycline was interpreted according to the Food and Drug Administration breakpoints. The isolates were classified as extended-spectrum β-lactamases (ESBL) producers if the zone diameter for ceftazidime was ≤22 mm and ≤27 mm for cefotaxime.
String test was performed for the detection of hypervirulent K. pneumoniae and was defined positive when a viscous string of >5 mm was produced when the colonies were stretched with an inoculation loop.
The bacterial DNA was extracted using the automated QIAsymphony (Qiagen) extractor as described by manufacturer. Molecular characterisation of bacterial isolates was carried out using conventional multiplex polymerase chain reaction (PCR) for the detection of ESBLs which includes blaSHV, blaTEM, blaVEB, blaPER and blaGES genes as described by Dallenne et al., 2010. Multiplex PCR for CTX-M consisting of blaCTX-M-1, blaCTX-M-2, blaCTX-M-8, blaCTX-M-9 and blaCTX-M-25 was done as described by Woodford et al., 2004. Multiplex PCR for AmpC including the blaACC, blaACT, blaDHA, blaCIT, blaMOX and blaFOX was done as described by Pérez-Pérez and Hanson, 2002. Carbapenemase genes which included blaIMP, blaVIM, blaNDM, blaSPM, blaOXA48-like and blaKPC were described by Poirel et al., 2011, Dallenne et al., 2010, Yigit et al., 2001 and Ellington et al., 2007.,,, The presence of outer membrane proteins, i.e. ompK35 and ompK36 was also determined by monoplex PCRs as described by Kaczmarek et al., 2006, since the absence/mutation in these porins contributes to antimicrobial resistance.
The K. pneumoniae isolates were also characterised for hypervirulence makers such as rmpA and rmpA2 apart from string test. PCR was performed as described by Brisse et al.
Multilocus sequence typing
Multilocus sequence typing was performed as described by Diancourt et al., 2005. The sequence types were assigned using the database provided at http://bigsdb.pasteur.fr/perl/bigsdb/bigsdb.pl?db=pubmlst_klebsiella_seqdef_public & page=profiles.
The relatedness of the predicted sequence types was investigated by eBURST V3 software (http://eburst.mlst.net/) employing the BURST algorithm.
Inc plasmid typing
Inc plasmid typing was performed to determine the presence of plasmids such as IncFIA, IncA/C, IncN and IncL/M, as described by Carattoli et al. PCR for IncFII and IncFII (K) was performed as described by Villa et al. Isolates known to harbour plasmids obtained through whole genome sequencing at the study centre were used as control strains for plasmid typing PCR.
Clinical and demographic details of patients
Clinical details of the patients were obtained from electronic medical records available at Christian Medical College, Vellore, and from the sepsis registry. Pro forma was developed, data entered in EpiData Entry v 3.0 to rule out errors such as repeat entry. Antibiotic susceptibility profiles and dates for all positive blood cultures were recorded. For each antibiotic, the dose, frequency and duration were documented. In bacteraemic patients, repeat blood cultures following the index blood cultures were recorded to document microbiological clearance. The data were analysed using EpiData Analysis software v 3.0.
| ~ Results|| |
Eleven isolates were ESBL producers, while two, isolate 3 and isolate 12, were pan-susceptible isolates. The isolates were resistant to minocycline and susceptible to tigecycline. None of the isolates was found to be carbapenem resistant. Isolates 2, 3, 11, 12 and 13 were susceptible to chloramphenicol. All but isolate 9 were susceptible to amikacin. Except isolates 3 and 12 which were pan-susceptible, others were resistant to gentamicin, netilmicin and ciprofloxacin. All the isolates were negative for string test, phenotypic marker for hypermucoviscous strains.
Results of molecular characterisation are listed in [Table 1]. All the isolates harboured blaSHV and blaTEM genes. blaCTX-M-1 was present amongst 12 of the 13 isolates. None of the isolates produced any of the AmpC and carbapenemase enzymes. Outer membrane protein, ompK35 was present in all the isolates while ompK36 was absent in all but one.
|Table 1: Results of molecular characterisation of resistance mechanisms, sequence typing and plasmid typing for IncFIIK|
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All the isolates lacked the rmpA and rmpA2 genes which are molecular markers of hypervirulence
Multilocus sequence typing
Ten isolates belonged to ST48 and one isolate each belonged to ST29, ST111 and a novel sequence type 2647. eBURST analysis is shown in [Figure 1]. Although the isolates were obtained in a span of 2 months, the four clonal types obtained were not belonging to the same clonal complex and were distinct from each other.
|Figure 1: eBURST of 13 Klebsiella pneumoniae isolates belonging to four different clonal types. Although the isolates were obtained in a span of 2 months, the clonal types obtained were not belonging to the same clonal complex and were distinct from each other as highlighted in the figure|
Click here to view
Inc plasmid typing
Six isolates belonging to ST48 were found to harbour IncFII (K) as mentioned in [Table 1] while none of the other plasmids such as IncFIA, IncFII, IncL/M, IncN and IncA/C was present in any of the isolates.
Clinical and demographic details of patients
Clinical and demographic details of patients are listed in [Table 2]. There were ten newborns who were later found to be infected with the same clone of K. pneumoniae. In retrospect, isolate 1 was probably the index case. This was a newborn who had early-onset sepsis with K. pneumoniae and presented on the day of birth with respiratory distress/pneumonia. The baby had an uneventful course thereafter and was discharged after 14 days of antibiotics. The other nine babies who developed late-onset sepsis were all preterm (gestation age range: 30–36 weeks) with birth weights ranging from 1240 to 2300 g [Table 2]. All these babies had septic shock or multiorgan dysfunction syndrome with sepsis. All excepting one baby had multiple cultures and took an average of 9.8 days for the blood to become sterile despite antibiotic regimens based on antibiogram. Four babies died, three due to sepsis and the fourth due to short-bowel syndrome following intestinal surgery for multiple intestinal atresias. Three babies did not show a negative culture before death. Sepsis-related mortality during this outbreak was thus 30%.
|Table 2: Clinical profile of the babies with Klebsiella pneumoniae sepsis|
Click here to view
Eight of the babies with sepsis with the ST48 strain received meropenem (40 mg/kg/dose twice daily) and seven received colistin (50,000 U/kg/dose twice daily). Only one of the babies with non-ST48 strain sepsis received meropenem and none received colistin [Table 2].
Of the three babies with non-ST48 sepsis, two were term babies and one was preterm. Of these babies, two had early-onset sepsis and one (isolate 13) had late-onset sepsis. All these babies survived.
During the outbreak, surveillance swabs were taken from 76 sites in the neonatal unit including the washbasins, various equipment (ventilators, ultrasound machines, telephones, humidifiers, oxygen ports, warmers, incubators and laminar flow) as well as patient intravenous lines, unopened intravenous fluids and ultrasound gel. K. pneumoniae was isolated from one weighing scale, a surface swab from the step-down nursery and the forceps solution in ICU. Before these results, intensive teaching in hand asepsis and aseptic non-touch technique were initiated and compliance monitored. The outbreak was terminated with these measures. Following the results of the surveillance testing, the use of forceps solution was discarded and intensive cleaning of ICU was done. Unfortunately, the isolates were not preserved for correlating with the clinical isolates.
| ~ Discussion|| |
Amongst 13 isolates of K. pneumoniae isolated from neonates over a span of 2 months, ten were found to belong to the same clone ST48 suggesting an outbreak. Overall, 12 of the 13 K. pneumoniae isolated were ESBL producers coding for SHV, TEM and CTX-M-1 enzymes. Isolate belonging to ST111 lacked the β-lactamase genes seen in other isolates. Apart from these β-lactamases, all the isolates except the one belonging to ST111 also lacked ompK36 which contributes to cephalosporin and carbapenem resistance. In India, SHV, TEM and CTX-M β-lactamases are commonly seen amongst K. pneumoniae isolates.,,, SHV is intrinsically produced by K. pneumoniae while TEM and CTX-M are plasmid-encoded enzymes.blaCTX-M-15 which belongs to blaCTX-M-1 group has been reported amongst IncF including IncFII, IncFIA and IncFIIK plasmids in K. pneumoniae.,, They have also been reported amongst IncL/M and IncHI1 plasmids.blaTEM has also been reported amongst IncFIA, IncFII, IncL/M, IncA/C and IncN. However, in the present study, only 6 isolates with blaTEM and blaCTX-M-1 harboured IncFIIK plasmid and other plasmids looked for under the study were found to be absent.
ompK35 and ompK36 have known to be associated with β-lactam resistance in K. pneumoniae. In India, there is a lack of data on the contribution of porins to antimicrobial resistance amongst K. pneumoniae. Shakib et al. studied the prevalence of these porins in ESBL and non-ESBL producing isolates and found that the susceptibility ceftazidime was linked to the presence of ompK35, and cefotaxime susceptibility was associated with ompK36. Hence, the presence/absence of these helps to determine the right cephalosporin to be chosen for therapy. Tsai et al., in their study, demonstrated that the single deletion of ompK36 resulted in minimum inhibitory concentration (MIC) shifts of cefazolin, cephalothin and cefoxitin from susceptible to resistant while the single deletion of ompK35 had no significant effect. In the present study, all the isolates belonging to ST48 and one each belonging to ST29 and ST2469 lacked ompK36 which make them more resistant to cephalosporins than the isolate belonging to ST111 in which ompK36 was present. Chen et al. demonstrated in mouse models that the insertional inactivation of ompK36 leads to 100-fold decrease in lethal dose-50 for virulent K1 K. pneumoniae.
In a neonatal sepsis outbreak in Tanzania, ST48 has been reported to carry blaTEM and blaCTX-M genes. A new sequence type ST2467 was assigned during the present study. The study also reports blaTEM and blaCTX-M genes to be carried by IncF plasmids such as IncFIA and IncFII. In the present study, though none of the isolates carried IncFIA, IncFII(K) was present amongst 6 isolates all of which belonged to ST48. ST111 isolate did not carry blaCTX-M gene and was pan-susceptible carrying ompK36. Earlier, ST111 has been reported amongst ESBL and carbapenem-resistant isolates.,, ST29 has also been reported amongst carbapenem-resistant isolates carrying blaTEM and blaCTX-M genes. Earlier in the study centre, there have been three new sequence types assigned amongst hypervirulent K. pneumoniae one of which was from a neonate. This shows that organism has been constantly evolving, and like the previous novel sequence types assigned at the study centre, the isolate ST2467 is pan-susceptible. Hence, even amongst pan-susceptible and ESBL K. pneumoniae, there is constant evolution which is worrisome as these can acquire carbapenem resistance in settings like ours where the carbapenem resistance rate is 32%.
Early-onset neonatal sepsis can be transplacental or due to vaginal flora entering uterus. Three cases amongst the 13 isolates were early-onset sepsis; one each belonging to ST29, ST48 and ST111. Other ten were due to late-onset sepsis which occurs due to exposure to flora of hospital environment, healthcare workers and family members. Lack of hand hygiene is one of the most common sources of neonatal infections. Preterm infants with low birth weight have a 3–10 times higher incidence of infection than full-term normal birth weight infants. Furthermore, preterm babies are exposed to prolonged intravenous access, endotracheal intubation or other invasive procedures which pose a risk for hospital-acquired sepsis. Most of the cases in the present study were low birth weight babies predisposing for infections. The birth weight of infants ranged from 1.2 to 3.3 kg [Table 2].
Empirically penicillin, cefoperazone-sulbactam and an aminoglycoside were administered to all the babies which were later modified later according to antibiogram. Ten babies received meropenem and colistin was administered as combination therapy in 7. A combination of tigecycline and colistin was administered in one infant. Tigecycline and colistin are the only alternatives for carbapenem-resistant isolates. Overall, sepsis-related mortality rate was 30% (4/13). Another Indian study shows 70% mortality amongst neonates with ESBL K. pneumoniae sepsis.
An outbreak involving six cases in 2 months in neonatal ICU due to K. pneumoniae from Italy has been reported. They improved the infection control measures and were able to curb the outbreak. Similar to the present study, K. pneumoniae producing SHV, TEM and CTX-M has caused an outbreak in North India in NICU. The mortality rate in this study was 63% (7/11), but the clonality of the isolates and plasmid profile were not investigated. Morality rate in the present study was 30%. Environmental samples from NICU and labour room also yielded K. pneumoniae similar to the present study.
| ~ Conclusion|| |
Ten of the 13 isolates belonging to ST48 with similar phenotypic and molecular characteristics isolated over a span of 2 months imply the K. pneumoniae outbreak amongst neonates. ESBL K. pneumoniae is commonly seen in Indian hospitals and the main mechanisms being production of SHV, TEM and CTX-M enzymes as seen in the present study. TEM and CTX-M contribute to plasmid-mediated resistance amongst K. pneumoniae. Outer membrane porins contribute significantly to antimicrobial resistance, but studies in the Indian setting are limited. Emergence of new clones though susceptible to antimicrobials implies the continuous evolution of the organism and also the potential for rapid genetic recombination leading to multidrug-resistant isolates. Outbreaks, especially amongst the neonates, lead to fatal outcome, and hospital infection control plays a critical role to curb outbreaks.
We thank the team of curators of the Institute Pasteur MLST system (Paris, France) for importing novel alleles, profiles and/or isolates at http://bigsdb.web.pasteur.fr.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2]