|Year : 2020 | Volume
| Issue : 1 | Page : 38-45
Is Superbug imminent? Findings of a retrospective study in Bangladesh
Sanjoy Kumer Dey1, Mohammad Kamrul Hassan Shabuj1, Ismat Jahan1, Humayra Akter1, Mohosina Akhter2
1 Department of Neonatology, Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh
2 Department of Neonatology, Mymensingh Medical College, Mymensingh, Bangladesh
|Date of Submission||03-Aug-2019|
|Date of Decision||12-Oct-2019|
|Date of Acceptance||07-Nov-2019|
|Date of Web Publication||29-Jan-2020|
Dr. Sanjoy Kumer Dey
Department of Neonatology, Room No 218, First Floor, Block C, Bangabandhu Sheikh Mujib Medical University, Shahbagh, Dhaka
Source of Support: None, Conflict of Interest: None
Background: Emergence of multidrug-resistant (MDR) neonatal sepsis is a potential threat to the survival of newborn babies. Hence, periodic evaluation of the drug resistance organisms responsible for neonatal sepsis is essential for appropriate management and prevention. Objective: This study was conducted to determine the antibiotic-resistant pattern of isolates from blood culture in neonates and their outcome in terms of death. Materials and Methods: This retrospective study was conducted in the neonatal intensive care unit (NICU) of Bangabandhu Sheikh Mujib Medical University from October 2014 to December 2017 for a period of 38 months. During the study period, of 1829 records of admitted patients, 559 cases were found to be suggestive of sepsis. Only blood cultures positive cases were analyzed in this study. Results: Culture-proven sepsis was documented in 124 cases among 559 (22.2%). Majority were late-onset sepsis (LOS), i.e., 113/124 (91.1%); remaining were early onset sepsis (EOS). Acinetobacter (46%) was found to be the most common organism in both early and LOS. Most of the organisms were resistant to 1st- and 2nd-line antibiotics. Colistin exhibited the highest sensitivity (91% in EOS and 94% in LOS). The prevalence of MDR and extended drug-resistant (XDR) organisms were 77.4% and 51.6%, respectively. When outcome was compared between nondrug resistance and MDR group, no death was documented among nondrug resistance (P < 0.001). Similarly, death was significantly higher among XDR when compared with nondrug resistance counterpart (P < 0.001). Conclusion: Acinetobacter, Klebsiella, and Escherichia coli are the leading causes of drug-resistant bacterial sepsis in NICU. There is high prevalence of MDR and XDR organisms. Death was significantly higher among MDR and XDR sepsis when outcome was compared with nondrug resistance counterpart.
Keywords: Death, extended drug resistance, multidrug resistance, neonatal sepsis
|How to cite this article:|
Dey SK, Shabuj MK, Jahan I, Akter H, Akhter M. Is Superbug imminent? Findings of a retrospective study in Bangladesh. J Clin Neonatol 2020;9:38-45
|How to cite this URL:|
Dey SK, Shabuj MK, Jahan I, Akter H, Akhter M. Is Superbug imminent? Findings of a retrospective study in Bangladesh. J Clin Neonatol [serial online] 2020 [cited 2020 Apr 7];9:38-45. Available from: http://www.jcnonweb.com/text.asp?2020/9/1/38/277229
| Introduction|| |
Neonatal sepsis is one of the major causes of neonatal mortality and morbidity worldwide. Despite considerable progress in hygiene, introduction of new antimicrobial agents, and advanced measure for early diagnosis and treatment, neonatal septicemia continues to be a major problem in neonatal intensive care units (NICUs) around the world. Incidence of neonatal sepsis varies from country to country, but it is much higher in developing countries than in developed nations. In Bangladesh, it contributes to about 19% of total neonatal deaths.
The etiology of neonatal sepsis and their sensitivity pattern changes over times and varies from region to region.,, Increasing antimicrobial resistance against commonly used antibiotics has been reported in many studies., Selection of suitable antimicrobial agents, which is the mainstay of treatment for septicemia, has become a biggest challenge for the neonatologists.
Early diagnosis and prompt administration of appropriate antimicrobial therapy to patients with septicemia has been shown to reduce mortality and morbidity., Hence, the choice of empirical antimicrobial therapy for septicemia must include knowledge of the sensitivity pattern of the pathogens associated with sepsis. Hence, periodic evaluation of organisms responsible for neonatal sepsis is essential for the appropriate management of neonatal sepsis.
Therefore, this study has been carried out to determine the clinical presentation, bacteriological profile, and antibiotic resistant pattern of isolates from blood culture in neonates admitted in NICU of Bangabandhu Sheikh Mujib Medical University (BSMMU) and their outcome in terms of death with a view to reduce practice of inappropriate use of antibiotics. This in turn would be cost-effective and hazardless endeavor to reduce neonatal morbidities and mortalities.
| Materials and Methods|| |
This was a retrospective study over a period from October 2014 to December 2017 in the NICU of BSMMU. Clinical records of all neonates with clinical features and/or risk factors of sepsis were retrieved. Sepsis screen and blood culture were collected. Clinical records of newborn having positive blood culture were included in this study.
Diagnosis of neonatal sepsis was based on the presence of antenatal risk factors and/or signs and symptoms of sepsis. Antenatal risk factors which were considered were (i) prolonged rupture of membrane (>18 h), (ii) foul-smelling and/or meconium-stained liquor, (iii) febrile illness of the mother with evidence of bacterial infection within 2 weeks before delivery, (iv) single unclean or >3 sterile vaginal examination(s) during labor, (v) prolong labor (sum of 1st and 2nd stage of labor >24 h), and (vi) perinatal asphyxia (APGAR score <4 at 1 min).
Documented clinical features of sepsis were lethargy, vomiting, abdominal distension, respiratory distress, temperature instability (hypothermia/fever), poor perfusion, hypo and hyperglycemia, bleeding manifestation, apnea, seizures, and jaundice.
Blood culture was performed by taking two ml venous blood in a culture bottle containing Trypticase soya broth for bacteriological culture in Microbiology laboratory of BSMMU, where standard technique was followed. Data of the culture-positive cases regarding gestational age, birth weight, sex, place of delivery, mode of delivery, clinical presentation, type of sepsis, name of the organism isolated with its sensitivity pattern, and outcome were recorded in a data collection sheet. Cases were classified as early-onset sepsis (EOS) if onset of sepsis within 72 h of life and late-onset sepsis (LOS) if onset after 72 h of life. Multidrug-resistant organisms (MDRO) and extended drug-resistant organisms (XDRO) were identified according to the definitions created by experts from the European Centre for Disease Prevention and Control and the Centers for Disease Control and Prevention. Multidrug resistant (MDR) was defined as nonsusceptibility to at least one agent in three or more antimicrobial categories. Extended drug resistant (XDR) was defined as nonsusceptibility to at least one agent in all but two or fewer antimicrobial categories (i.e., bacterial isolates remain susceptible to only one or two categories). Thus, a bacterial isolate that was characterized as XDR was also characterized as MDR. Outcome was measured in terms of death.
Data analysis was done using statistical package for social sciences (SPSS) software version 20.0 (SPSS Inc., IL, USA). Clinical features and final outcome of patients with sepsis due to MDROs and XDROs with those caused by non-MDROs were compared using Chi-square test. The level of significance for tests was set at P < 0.05.
| Results|| |
Of 1829 records of admitted patients, 559 cases were found to have clinically suggestive septicemia. Among them, culture-proven sepsis was 124 cases (22.2%). Five patients were positive for 2 organisms on separate occasions. Majority were LOS, i.e., 113/124 (91.1%); remaining were EOS. Among the culture-positive cases, preterm babies outnumbered the term babies (65.5% vs. 34.5%); low birth weight (LBW), very LBW, and extremely LBW babies together constituted 68% of the cases; majority of the patients were delivered by lower uterine caesarian section (LUCS) (75.6%); inborn babies outnumbered the outborns (64.7% vs. 35.3%); and male: female ratio was 1.5:1. Baseline characteristics of the culture-positive cases are presented in [Table 1].
Clinical presentations of the culture-positive cases with their frequencies are presented in [Table 2]. The most common clinical presentation was lethargy, i.e., 82.3%. Next to lethargy, temperature instability was presenting feature in 38% cases followed by respiratory distress and apnea in 32.3% and 28.2%, respectively.
Comparison of clinical presentation between early and LOS is shown in [Figure 1] which showed respiratory distress was the most common among EOS cases (72.7%).
|Figure 1: Distribution of clinical presentation among early- and late-onset sepsis cases|
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In this study, Gram-negative organism was responsible for 95.2% of the culture-proven sepsis.
Acinetobacter (46%) was the most frequently isolated organism in case of both early and LOS followed by Klebsiella (37.9%) and Escherichia coli (6.5%). Less frequently encountered organisms were Streptococcus spp. (1.6%), Staphylococcus haemolyticus (3.2%), and other Gram-negative organisms (4.8%). Organisms isolated along with their relative frequencies are given in [Table 3].
[Figure 2] shows the pattern of organism isolated by year. It was observed that in the year 2015 and 2016, Acinetobacter was the most frequently isolated organism; but in the year 2017, Klebsiella was accountable for most of the culture-positive sepsis.
Antibiotic sensitivity pattern of the organisms in relation to early and LOS is described in [Table 4]. Colistin showed the highest sensitivity; 91% in EOS and 94% in LOS followed by tazobactam-piperacillin 73% in EOS versus 53% in LOS, ciprofloxacin 45.5% in EOS versus 44% in LOS, netilmicin 73% in EOS versus 41% LOS, and imipenem 45.5% in EOS versus 42% in LOS. When individual antibiotic sensitivity was compared in relation to onset of sepsis, ampicillin (P = 0.04) and netilmicin (P = 0.04) were significantly more sensitive in early onset than LOS.
|Table 4: Comparison of antibiotic sensitivity in relation to early- and late-onset sepsis (n=124)|
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Antibiotic sensitivity pattern was observed throughout the period of 2015 to 2017 which showed sensitivity to Colistin was similar and close to 100%. Sensitivity to carbapenem showed decreasing trend during the period whereas netilmicin sensitivity increased slightly in the year 2017. A small upward trend of sensitivity was noted in case of piperacillin-tazobactam and ciprofloxacin in 2016 which decreased afterward in the subsequent year [Figure 3].
|Figure 3: Pattern of antibiotic sensitivity for the commonly sensitive antibiotics|
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Sensitivity of the 3 organisms to commonly used antimicrobial agents is shown in [Table 5]. Acinetobacter showed 94.7% sensitivity to colistin followed by netilmicin 51% and carbapenem 47.4%. Acinetobacter sensitivity was similar 45.6% in case of ciprofloxacin and tazobactam-piperacillin. Acinetobacter were 100% resistant to ampicillin. Klebsiella showed 100% resistance to ampicillin and 3rd-generation cephalosporins. It showed 89.3% sensitivity to colistin, followed by ciprofloxacin 57.4%, tazobactam-piperacillin 44.6%, netilmicin 40.4%, and imipenem 34%. E. coli showed 100% sensitivity to colistin followed by imipenem (75%) and tazobactam-piperacillin (62.5%).
|Table 5: Sensitivity of the 3 common organisms to antimicrobial agents (n=124)|
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Higher frequencies of MDR and XDR organisms among culture-positive cases were observed in this study. Nearly, three-forth organisms were MDR (77.4%) and half were XDR (51.6%) [Table 6].
|Table 6: Frequency of multi drug resistant and extended drug resistant organism (n=124)|
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[Table 7] shows the comparison between early and LOS. In preterm and LBW babies, LOS was significantly more common in comparison to term and appropriate for gestational age babies (P = 0.005 and 0.02, respectively). There was no significant difference in terms of outcome and drug-resistant pattern between the two groups.
|Table 7: Comparison of clinical parameters and drug resistance pattern between early- and late-onset sepsis (n=124)|
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Comparison of clinical characteristics and outcome caused by MDR and XDR organisms are presented in [Table 8] and [Table 9], respectively. Prematurity, LBW, outborn, and male infants were more frequently observed among sepsis by MDR organism when compared to non-MDR counterpart, although the differences were not statistically significant. When outcome was compared in terms of death between nondrug resistance and MDR group, no death was documented among nondrug resistance (P < 0.001). Findings were similar when comparison was studied among XDR cases with non XDR counterpart (5.9% death vs. 94.1%, P < 0.001) [Table 9].
|Table 8: Comparison of clinical characteristics and outcome of multidrug-resistant patients (n=124)|
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|Table 9: Comparison of clinical characteristics and outcome of extended drug resistant patients (n=124)|
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[Figure 4] shows that during the study period, MDR organism showed slight decreasing trend (83.3%–71.4%), while XDR organism increased over time with a peak of 60% during the year 2016 (45.8%–52.3%).
Death among XDR was proportionately higher compared to those in MDR, but the difference was statistically insignificant (50% vs. 35.4%, P = 0.07) [Table 10].
|Table 10: Outcome of multidrug resistant and extended drug-resistant patients (n=124)|
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| Discussion|| |
Neonatal sepsis is a life-threatening condition, and any delay in treatment may result in significant morbidity and mortality. The rapid emergence of MDR neonatal sepsis is a potential threat to the survival of newborn babies. Continued local surveillance is crucial to monitor emergence of bacterial resistance.
The culture positivity rate in this study was found to be 22.2%. It was nearly similar to other studies.,,, It was higher than the rate reported from BIRDEM, a tertiary care hospital in Dhaka, by Raha et al. (8.9%) but lower than the rate reported from Dhaka Shishu Hospital by Ahmed et al. (35%) and from Nepal (28%) by Jain et al. and from India (42%) by Kumhar et al. A low blood culture isolation rate could be due to administration of antibiotic before blood collection.
In this study, only 11 (8.9%) patient had EOS, remaining 113 (91.1%) had LOS. A lower rate of culture positivity in EOS compared to LOS (35.4% and 54.6%) was previously reported from BIRDEM by Begum et al. and few studies from other countries. However, this finding is in contrast with many other studies where culture positivity rate was more in EOS.,, Possible explanation of increasing percentage of EOS in some of the study article might be due to timing of EONS; some authors define EOS up to the age of first 7 days.
Majority of the culture-positive newborns were preterm (65.5%) and LBW (68%). This is an agreement with other studies from Bangladesh, and other developing countries. Sepsis was more common in these groups of neonates as they are more vulnerable to infection due to immaturity of immune system, prolonged hospital stay, and use of equipment such as continuous positive airway pressure, ventilator, and intravenous access.
In the current study, Gram-negative organisms were responsible for sepsis in most of the cases (95.2%). This finding is similar to other studies from Bangladesh, and other developing countries.,,Acinetobacter (46%) was the most common organism followed by Klebsiella (37.9%) and E. coli(6.5%). This finding is consistent with that of Yusef et al. and Alam et al. where Acinetobacter was the most frequent organism responsible for Gram-negative sepsis. However, in a previous study in BIRDEM, Begum et al. found Klebsiella was the most common organism (52.3%), followed by Enterobacter (21.5%) and Acinetobacter (10.8%). Raha et al. also found Klebsiella is the most frequently encountered organism among the culture-positive cases. However, Rahman et al. found both Acinetobacter and Klebsiella with equal frequency (27.3%) which was followed by E. coli(18.2%).
Our study showed a high degree of resistance to first- and second-line antibiotics used in neonatal sepsis which is an agreement with the previous studies from BSMMU by Rahman et al. and Begum et al. and with many recent studies from other developing countries.,,, There is emerging resistance against third-line antibiotics including ciprofloxacin, imipenem, netilmicin, and tazobactam-piperacillin. Begum et al. found around 15% resistance to carbapenem group which is the most commonly used third-line antibiotic. However, in our study, carbapenem resistance is found to be 58.1%, and also, resistance is increasing over years [Figure 1]. Al-Lawama et al. published a descriptive study on 21 patients (from NICU in another medical institution in Jordan) with culture-proven Acinetobacter baumannii sepsis, 90% of which were resistant to carbapenems. It is an alarming situation that organisms are developing resistance to most of our third-line antibiotics. In our study, colistin is the only antibiotic with satisfactory sensitivity profile (93.5%) which was similar to the finding of Yusef et al.
In the current study, Acinetobacter was 100% resistant to ampicillin and highly resistant to aminoglycosides and third-generation cephalosporin, moderately resistant to fluoroquinolone and carbapenem. Begum et al. also found 100% resistance to ampicillin, but resistance to most of the 2nd- and 3rd-line antibiotics was lower than the present study. This indicates that this organism is developing more resistance over time. Klebsiella showed a greater degree of resistance to all the antibiotics compared to others with 100% resistance to ampicillin, gentamicin, and the 3rd-generation cephalosporins. This finding is comparable to the findings of Begum et al.
When early and LOS were compared, it was found that LOS was significantly more common in preterm and LBW infants (96.3% and 95.2%, respectively) in comparison to term and appropriate for gestational age babies, consistent with the findings of Begum et al. Similar findings were noted from studies of neighboring countries such as India and Nepal., In this study, mortality was more in the LOS group (94.1%), comparable with the findings of Ahmed et al.
The most alarming finding of this study is the high proportion of MDR and XDR organism. Most of the organisms (77.4%) were MDR, and about half (51.6%) of the organisms were XDR. The percentage of MDR is higher than that found by Tsai (18.6%) and Yusef et al. (69%). Prematurity, LBW, outborn, and male infants were more frequently observed among sepsis by MDR organism when compared to non-MDR counterpart, although the differences are not statistically significant. Death was significantly associated in MDR sepsis when compared with sepsis with non-MDR counterpart (0% vs. 100%, P < 0.001). Findings were similar when comparison was studied among XDR cases with non-XDR counterpart (5.9% death vs. 94.1%, P < 0.001) [Table 8]. In this study, deaths in newborn due to XDR were proportionately higher compared to those in MDR, but the difference was statistically insignificant (50% vs. 35.4%, P = 0.07).
The high prevalence of antimicrobial resistance rates noted in our study might be due to indiscriminate and overuse of drugs in our country because of their easy over-the-counter availability. In the light of above findings, there remains a growing need for novel agents, although a recent study from India reported polymyxin, chloramphenicol, and cotrimoxazole are being revisited as possible choices of treatment.
| Conclusion|| |
Gram-negative bacteria, in particular Acinetobacter, Klebsiella, and E. coli are the leading causes of neonatal sepsis in this study. Most of the organisms showed high level of resistance to ampicillin, gentamicin, and third generation of cephalosporin and emerging resistance against 3rd-line antibiotics such as carbapenem, tazobactam-piperacillin, ciprofloxacin, and netilmicin. There is high prevalence of MDR and XDR organisms. No death was documented among nondrug resistance when outcome was compared with MDR sepsis (0% vs. 100%, P < 0.001). Similarly, death was significantly higher among XDR when compared with nondrug resistance counterpart (5.9% death vs. 94.1%, P < 0.001). Deaths in newborn due to XDR was proportionately higher compared to those in MDR, but the difference was statistically insignificant (50% vs. 35.4%, P = 0.07). Therefore, ongoing surveillance of local epidemiology and antimicrobial susceptibility is essential to ensure appropriate empiric and targeted antimicrobial therapy.
Sepsis due to MDROs constitutes a significant health care problem and causes significant mortality in the NICU. Therefore, a crucial approach is to continuously evaluate the dose, duration, and the indication of these broad-spectrum antibiotics. Another important step is to implicate antimicrobial stewardship programs and infection control polices to achieve judicious use of antibiotics in the NICU.
We want to express our gratitude to Professor Mohammod Shahidullah, the Chairman department of Neonatology for his continuous guidance. We are also grateful to all faculties, doctors, nurses, and staff of the Department of Neonatology, Bangabandhu Sheikh Mujib Medical University for their contribution in patient care.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7], [Table 8], [Table 9], [Table 10]