|Year : 2014 | Volume
| Issue : 4 | Page : 200-204
Pattern and antimicrobial susceptibility of carbapenem resistant organisms in tertiary care neonatal intensive care unit, India
Aravanan Anbu Chakkarapani1, Prakash Amboiram2, Umamaheswari Balakrishnan2, Binu Ninan2, Uma Sekar3
1 Department of Pediatrics, Division of Neonatology, McMaster University, Hamilton, Ontario, Canada, Canada
2 Department of Pediatrics, Sri Ramachandra Medical College, Chennai, Tamil Nadu, India
3 Department of Microbiology, Sri Ramachandra Medical College, Chennai, Tamil Nadu, India
|Date of Web Publication||14-Nov-2014|
Aravanan Anbu Chakkarapani
Department of Pediatrics, Division of Neonatology, McMaster University, Hamilton, Ontario L8S 1A9
Source of Support: None, Conflict of Interest: None
Background: The emergence of carbapenem resistant organism (CRO) in the health care setting has been well-documented recently. CRO is an increasing cause of neonatal infections all over the world especially in developing countries. Objective: The aim was to study pattern, incidence, and antimicrobial sensitivity of CROs in neonatal Intensive Care Unit (NICU). Materials and Methods: We conducted a retrospective observational study between January 2011 and June 2012. The study was conducted at a tertiary level NICU. Blood cultures were done in BACTEC 9120 or brain heart agar. Culture isolates were identified by automated identification or conventional biochemical tests. Microscan 96 and/or disk diffusion method performed antibiotic susceptibility. We studied the entire Gram-negative blood culture positive isolates and also studied their antibiotic sensitivity pattern. CRO was defined by any Gram-negative isolates showing resistant to meropenem and imipenem. Results: One hundred and thirty-four babies had grown microorganisms in their blood culture. Of the 134, 77.6% (n = 104/134) was due to Gram-negative organism infection. Among culture positive Gram-negative organisms, 14.4% (n = 15/104) babies had carbapenem resistant Gram-negative organisms infections. Among the CRO, most common was Acinetobacter species (n = 9), followed by Klebsiella pneumoniae (n = 4), Escherichia coli (n = 1), Serratia (n = 1). CRO showed resistance to our first line, second line drugs and carbapenems. Mortality among CRO babies was 33% (n = 5/15). Babies with nonCRO infection had 10% mortality (n = 9/89). All CROs were sensitive to Polymyxin and colistin. Conclusion: The incidence of CRO was surprising. Polymyxin B and E (colistin) is the drug of choice for CRO. Mortality among these CROs was greater than nonCRO. Mortality caused by CRO is knocking and shocking data, indicating the emergence to check the use of antimicrobials in NICUs.
Keywords: Carbapenem resistant organisms, neonatal infections, Antibiotic susceptibility
|How to cite this article:|
Chakkarapani AA, Amboiram P, Balakrishnan U, Ninan B, Sekar U. Pattern and antimicrobial susceptibility of carbapenem resistant organisms in tertiary care neonatal intensive care unit, India. J Clin Neonatol 2014;3:200-4
|How to cite this URL:|
Chakkarapani AA, Amboiram P, Balakrishnan U, Ninan B, Sekar U. Pattern and antimicrobial susceptibility of carbapenem resistant organisms in tertiary care neonatal intensive care unit, India. J Clin Neonatol [serial online] 2014 [cited 2021 Apr 14];3:200-4. Available from: https://www.jcnonweb.com/text.asp?2014/3/4/200/144750
| Introduction|| |
Neonatal deaths account for over a third of the global burden of child mortality.  In many developing countries neonatal mortality rates (deaths in the first 28 days of life) are as high as 40-50/1000 live births,  with infections being the major cause of death.  Sepsis is a significant cause of morbidity and mortality in neonates. 
Neonatal sepsis is defined as a disseminated disease with positive blood culture during the 1 st month of life,  and is more common in developing countries compared with developed countries. Sepsis with Gram-negative microorganisms is increasingly reported nowadays particularly in Asian countries. 
The inadvertent use of broad-spectrum antibiotics has led to the emergence of carbapenem resistant Gram-negative bacteria.  Klebsiella species, Acinetobacter species are of significantly important carbapenem resistant organism (CRO) showing resistant to most of the antibiotics.  The common pathogens of bacterial sepsis and antibiotic sensitivity patterns vary in different parts of the world. 
This study was undertaken to study the pattern, incidence and antimicrobial sensitivity of CRO from blood cultures of neonates admitted to tertiary level neonatal Intensive Care Unit (NICU).
| Materials and methods|| |
This is a retrospective observational study. An analysis was conducted of reports of all blood cultures obtained from the neonates who had suspected clinical sepsis admitted to the NICU at a tertiary care hospital for 18 months from January 2011 to June 2012. The unit is 40-bedded NICU serving both intramural (predominantly, more than 90% of total admissions) and extramural neonates. All neonates with suspected clinical sepsis were included in the study. Detailed records of the gestational age, age at onset, birth weight and culture positivity and the antibiogram of the organisms were noted in a proforma. Blood culture was taken from babies with suspected clinical sepsis before starting or changing antibiotics. Clinical sepsis in this study was defined as the presence of any one of the signs suggestive of sepsis such as, lethargy, apnea, tachypnea, tachycardia, hypotension, temperature instability, symptomatic hypoglycemia, hyperglycemia, change in oxygen requirement, poor perfusion, and abdominal distension with or without positive septic screen. 
Blood culture sample included a single sample collected from a peripheral vein under aseptic conditions. The local site was cleansed with povidone iodine (1%) and allowed to dry followed by 70% alcohol based antiseptic and allowed to dry. Blood volume of 1 ml was taken for each blood culture. Blood cultures were done either by BACTEC 9120 or brain heart agar. In BACTEC 9120, isolates were identified by automated identification and Siemens MicroScan± WalkAway±-96 Plus System performed antibiotic susceptibility. In brain heart agar, isolates were identified by conventional biochemical tests and antibiotic susceptibility was performed by disk diffusion method. 
Early onset neonatal sepsis (EONS) and late onset neonatal sepsis (LONS) is defined as clinical evidence of sepsis within 72 h or after 72 h after birth, respectively and blood culture grew an organism. Babies had same organism in the repeat culture and blood culture contaminants were excluded from the study. Antibiotics were changed according to the blood culture report and sensitivity pattern obtained in the antibiogram and also based on clinical response. If there were no growth after 5 days, it was considered as culture negative by Microbiologist. CRO was defined as any Gram-negative isolates showing resistant to meropenem and imipenem. We did cerebro spinal fluid analysis in all CRO sepsis babies. Outcome of the babies having CRO in terms of survival and complications like meningitis were recorded. We did not have a data on babies with carbapenem resistant among intramural and extramural deliveries.
During the study period, ampicillin and gentamicin were used as first line, amikacin and piperacillin and tazobactum as second line for EONS. Piperacillin and tazobactum and amikacin were used as first line in LONS. We used meropenem or imipenem to treat organisms resistant to our second line drugs. Carbapenems were started by physician based on blood culture sensitivity or clinical condition of the baby deteriorating in spite of adequate antibiotic cover. Once blood culture showed CRO, then we started Polymyxin B or colistin (Polymyxin E) and also very occasional cases we started Polymyxin B or colistin (Polymyxin E) based on poor clinical condition of the baby not responding to carbapenems.
| Results|| |
During the study period, total numbers of live births were 5410. NICU admission was 2720, Sepsis occurred in 4.9% babies (n = 134) of all NICU admissions. Blood culture yield rate was 9.3%. Neonatal sepsis rate was 24/1000 live birth (n = 134). NICU mortality was 7.7/1000 live birth (n = 42), out of this sepsis mortality rate was 42% (n = 18/42).
Of 134 babies with culture positivity 77.6% (n = 104) were due to Gram-negative organism infection. Among culture positive Gram-negative organisms, 85.6% (n = 89/104) of babies with Gram-negative organisms were sensitive to carbapenems, 14.4% (n = 15/104) of babies had CRO. Pattern of CRO were shown in [Table 1]. Most common CRO was Acinetobacter species (n = 9), followed by Klebsiella pneumoniae (n = 4), Escherichia coli (n = 1), Serratia (n = 1).
Mortality among CRO babies was 33.33% (n = 5/15). Infections in all these five babies were caused by Acinetobacter species. Remaining 10 babies survived without any persistent complication such as meningitis, septic shock and multi organ failure. Mortality among nonCRO babies was 10% (n = 9/89).
Among the babies with CROs, EONS incidence was 33% (n = 5/15) and LONS incidence was 66% (n = 10/15). Mortality in EONS and LONS babies with CRO was 40% (n = 2/5) and 30% (n = 3/10), respectively.
Carbapenem resistant organism was 90-100% sensitive to either Polymyxin B or Polymyxin E (colistin). Carbapenem resistant Acinetobacter species were 10-30% sensitive to cefaperazone plus sulbactum, cefepime plus sulbactum, aztreonam, and levofloxacin. Carbapenem resistant K. pneumoniae was 50% sensitive to ciprofloxacin, levofloxacin, and aztreonam.
Antibiotic sensitivity and resistant pattern of carbapenem resistant Acinetobacter species and K. pneumoniae were shown in [Table 2] and [Table 3]. All babies with CRO were preterm <32 weeks and very low birth weight (VLBW) babies except one (term baby).
|Table 2: Carbapenem resistant Acinetobacter species antibiotic susceptibility pattern |
Click here to view
|Table 3: Carbapenem resistant Klebsiella pneumonia antibiotic susceptibility pattern |
Click here to view
| Discussion|| |
Carbapenem resistant organism has been reported worldwide and is now recognized as one of the most difficult health care associated infections to control and treat. In adults, Burn ward and ICU patients and those with central intravenous catheters are the main targets of this organism. , Several outbreaks of CRO in ICUs, burns units  and NICUs ,, have been reported previously. We report the pattern, incidence and antimicrobial sensitivity of CRO from NICU.
Von-Dolinger  has identified prematurity and extreme low birth weight as risk factors for developing infection with CRO infection in NICU. In our study except one baby all other babies were < 32 week and VLBW babies. Acinetobacter was the most common CRO similar to Saleem et al.  study. Interestingly five out of nine babies with carbapenem resistant Acinetobacter infection (approximately 50%) died in our study. Balkhy et al.  documented carbapenem-resistant K. pneumoniae outbreak in a tertiary care facility. Our study showed carbapenem resistant K. pneumoniae was the second most common. All of our babies with carbapenem resistant Klebsiella organism infections survived without any complication.
However, McGrath et al.  study discussed the CRO grown in eye swab, Endo tracheal tube secretions and blood culture, in our study we discussed only on CRO grown in blood cultures. Many studies mentioned about the nosocomial spread of CRO  in the intensive care unit. In our study, we observed that two-third of infection with CRO presented as late onset sepsis, this explains there could be a potential chance for horizontal transmission of these organisms. Interestingly we found one-third of these organisms in the early onset sepsis also, it indicate us that possibility of vertical transmission from mother.
Carbapenems were previously known to be effective against multi drug resistant organisms but since the emergence of CROs it is even more difficult to treat this organism. The Centers for Disease Control and Prevention reports an increasing rate of CROs from 9% in 1995 to 40% in 2004;  however, the drug resistance and organism virulence is different in different parts of the world.
Drug susceptibility testing in our study revealed resistance to all first-line and second line antibiotics and carbapenems. Polymyxins were not used in first-line susceptibility testing unless there was a resistance to carbapenems. All 15 of our study blood isolates showed resistant to carbapenems. Colistin or Polymyxin B was used in babies with carbapenem resistance pattern in blood culture or organism infection and also very occasional cases we started Polymyxin B or colistin (Polymyxin E) based on poor clinical condition of the baby not responding to carbapenems. , One-third of babies (n = 5/15) died in the study group, all of them died due to carbapenem resistant Acinetobacter species. Four out of five babies died in spite of starting these drugs. One baby was succumbed on day 2 of postnatal life, before starting on Polymyxin B or colistin, we received a positive blood culture after baby's demise. This indicates rapid spread of these organisms in the blood and high mortality. In our study we found that, mortality due to CRO were higher (33%) when compared to carbapenem sensitive group (10%). Prematurity and VLBW were associated with increased mortality. In our study, we did cerebro spinal fluid analysis in all CRO sepsis babies and we found it was negative. Interestingly in our study, few of carbapenem resistant Acinetobacter and Klebsiella were mild to moderate sensitivity to levofloxacin, ciprofloxacin, aztreonam, and sulbactum drugs.
There are certain limitations of our study. This was a single center study, and may not represent the findings at other NICU centers. Furthermore, we were not able to assess all the variables and were limited by the completeness of documentation by the treating physicians. This one center study has a limited number of patients so results should be generalized with caution. We did not perform any sub group analysis. We do not have the details of gene mutation of the CROs in this study.
| Conclusion|| |
Incidence of carbapenem resistance organisms in this study was 14.4%. Mortality among these CROs was very high when compared to nonCROs. High degree of antibiotic resistance was seen in Acinetobacter species and can be correlated with the fatality rate caused by them. All CROs were susceptible to Polymyxin B or colistin, but shown resistant to most of the third generation of cephalosporins and all carbapenems. High incidence of CROs in NICU was the striking feature of this study and justifies the purpose of the study.
| References|| |
|1.||Lawn JE, Cousens S, Bhutta ZA, Darmstadt GL, Martines J, Paul V, et al. Why are 4 million newborn babies dying each year? Lancet 2004;364:399-401. |
|2.||Hyder AA, Wali SA, McGuckin J. The burden of disease from neonatal mortality: A review of South Asia and Sub-Saharan Africa. BJOG 2003;110:894-901. |
|3.||Remington JS, Klein JO. Neonatal infections: A global perspective In: Infectious Diseases of the Fetus and Newborn Infant. 5 th ed. Philadelphia, PA: Saunders; 2001. p. 139-68. |
|4.||Stoll BJ. Infections of the neonatal infant. In: Nelson Textbook of Pediatrics. 17 th ed. Philadelphia: Saunders; 2004. p. 623-39. |
|5.||Edwards MS. Postnatal infections. In: Fanaroff and Martins Neonatal-Perinatal Medicine. 8 th ed. Philadelphia; Elsevier Mosby; 2006. p. 791-804. |
|6.||Vergnano S, Sharland M, Kazembe P, Mwansambo C, Heath PT. Neonatal sepsis: An international perspective. Arch Dis Child Fetal Neonatal Ed 2005;90:F220-4. |
|7.||Bakr AF. Intravenous lines-related sepsis in newborn babies admitted to NICU in a developing country. J Trop Pediatr 2003;49:295-7. |
|8.||Roilides E, Kyriakides G, Kadiltsoglou I, Farmaki E, Venzon D, Katsaveli A, et al. Septicemia due to multiresistant Klebsiella pneumoniae in a neonatal unit: A case-control study. Am J Perinatol 2000;17:35-9. |
|9.||Waheed M, Laeeq A, Maqbool S. The etiology of neonatal sepsis and patterns of antibiotic resistance. J Coll Physicians Surg Pak 2003;13:449-52. |
|10.||National Neonatal-Perinatal Database Report 2005. India: National Neonatology Forum. |
|11.||Clinical and Laboratory Standards Institute. Performance Standards for Antimicrobial Susceptibility Testing; Eighteenth Informational Supplement. CLSI Document M100-S18. Wayne, PA: Clinical and Laboratory Standards Institute; 2008. |
|12.||Simmonds A, Munoz J, Aguero-Rosenfeld M, Carbonaro C, Montecalvo M, Clones B, et al. Outbreak of Acinetobacter infection in extremely low birth weight neonates. Pediatr Infect Dis J 2009;28:210-4. |
|13.||Munoz-Price LS, Weinstein RA. Acinetobacter infection. N Engl J Med 2008;358:1271-81. |
|14.||Crowe M, Towner KJ, Humphreys H. Clinical and epidemiological features of an outbreak of acinetobacter infection in an intensive therapy unit. J Med Microbiol 1995;43:55-62. |
|15.||Chan PC, Huang LM, Lin HC, Chang LY, Chen ML, Lu CY, et al. Control of an outbreak of pandrug-resistant Acinetobacter baumannii colonization and infection in a neonatal intensive care unit. Infect Control Hosp Epidemiol 2007;28:423-9. |
|16.||Stone JW, Das BC. Investigation of an outbreak of infection with Acinetobacter calcoaceticus in a special care baby unit. J Hosp Infect 1986;7:42-8. |
|17.||Schloesser RL, Laufkoetter EA, Lehners T, Mietens C. An outbreak of Acinetobacter calcoaceticus infection in a neonatal care unit. Infection 1990;18:230-3. |
|18.||von Dolinger de Brito D, Oliveira EJ, Abdallah VO, da Costa Darini AL, Filho PP. An outbreak of Acinetobacter baumannii septicemia in a neonatal intensive care unit of a university hospital in Brazil. Braz J Infect Dis 2005;9:301-9. |
|19.||Saleem AF, Ahmed I, Mir F, Ali SR, Zaidi AK. Pan-resistant Acinetobacter infection in neonates in Karachi, Pakistan. J Infect Dev Ctries 2009;4:30-7. |
|20.||Balkhy HH, El-Saed A, Al Johani SM, Francis C, Al-Qahtani AA, Al-Ahdal MN, et al. The epidemiology of the first described carbapenem-resistant Klebsiella pneumoniae outbreak in a tertiary care hospital in Saudi Arabia: How far do we go? Eur J Clin Microbiol Infect Dis 2012;31:1901-9. |
|21.||McGrath EJ, Chopra T, Abdel-Haq N, Preney K, Koo W, Asmar BI, et al. An outbreak of carbapenem-resistant Acinetobacter baumannii infection in a neonatal intensive care unit: Investigation and control. Infect Control Hosp Epidemiol 2011;32:34-41. |
|22.||Dai W, Huang S, Sun S, Cao J, Zhang L. Nosocomial spread of carbapenem-resistant Acinetobacter baumannii (types ST75 and ST137) carrying blaOXA-23-like gene with an upstream ISAba1 in a Chinese hospital. Infect Genet Evol 2013;14:98-101. |
|23.||Carey RB, Banerjee SN, Srinivasan A. Multidrug-resistant Acinetobacter infections, 1995-2004. Presented at the 46 th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco; 2006. p. 27-30. |
|24.||Pagakrong LP, Teeratakulpisarn J, Kitkhuandee A. Carbapenem-resistant Acinetobacter baumannii septicemia and meningitis in a neonate treated with colistin and netilmycin. J Pediatr Infect Dis 2008;3:283-5. |
|25.||Li J, Nation RL, Turnidge JD, Milne RW, Coulthard K, Rayner CR, et al. Colistin: The re-emerging antibiotic for multidrug-resistant Gram-negative bacterial infections. Lancet Infect Dis 2006;6:589-601. |
[Table 1], [Table 2], [Table 3]
|This article has been cited by|
||Carbapenem-Resistant Klebsiella pneumoniae Outbreak in a Neonatal Intensive Care Unit: Risk Factors for Mortality
| ||Meltem Bor,Ozkan Ilhan |
| ||Journal of Tropical Pediatrics. 2020; |
|[Pubmed] | [DOI]|
||Clinical and Bacteriological Profile of Neonatal Sepsis: A Prospective Hospital-Based Study
| ||Jimba Jatsho,Yoriko Nishizawa,Dorji Pelzom,Ragunath Sharma |
| ||International Journal of Pediatrics. 2020; 2020: 1 |
|[Pubmed] | [DOI]|
||Modified combined disc test (mCDT): a novel, labor-saving and 4 times cheaper method to differentiate Class A, B and D carbapenemase-producing Klebsiella species
| ||Nitin Kumar,Varsha A Singh,Vikas Beniwal |
| ||Diagnostic Microbiology and Infectious Disease. 2018; |
|[Pubmed] | [DOI]|
||Modified Carba NP Test: Simple and rapid method to differentiate KPC- and MBL-producing Klebsiella
| ||Nitin Kumar,Varsha A. Singh,Vikas Beniwal,Shinu Pottathil |
| ||Journal of Clinical Laboratory Analysis. 2018; : e22448 |
|[Pubmed] | [DOI]|