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ORIGINAL ARTICLE
Year : 2019  |  Volume : 10  |  Issue : 2  |  Page : 178-183  

Pattern of antimicrobial usage in neonatal septicemia at neonatal intensive care unit of a tertiary care hospital in Kolkata


1 Department of Pharmacology, College of Medicine and Sagore Dutta Hospital, Kamarhati, West Bengal, India
2 Department of Microbiology, College of Medicine and Sagore Dutta Hospital, Kamarhati, West Bengal, India
3 Department of Paediatrics, Calcutta National Medical College, Kolkata, West Bengal, India
4 Department of Neurology, Institute of Neurosciences Kolkata, Kolkata, West Bengal, India

Date of Web Publication18-Jul-2019

Correspondence Address:
Nandita Pal
Department of Microbiology, College of Medicine and Sagore Dutta Hospital, Kamarhati, Kolkata-58, West Bengal
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jnsbm.JNSBM_5_19

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   Abstract 


Introduction: Antimicrobials are the mainstay treatment in neonatal septicemia (NS). National treatment guidelines for antimicrobial use in infectious diseases issued by the Government of India has paved the way for rationalizing antibiotic use, but it needs tailoring according to the prevalent local microbiota and individual patient's needs. A periodic surveillance of the microbial etiology and antibiotic use patterns in NS may be useful in rational selection of empirical antimicrobial therapy. Aims and Objectives: We observed the utilization pattern of antimicrobials and quantified the same in neonates admitted to neonatal intensive care unit (NICU) with septicemia along with the prospective follow-up of the clinical response to individual regimen. Materials and Methods: This hospital-based prospective observational study was conducted from January 2017 to June 2017 on 102 consecutive cases of NS admitted to NICU. Data regarding demographic parameters, antimicrobials used, and outcome were collected through a predesigned case record form. Antimicrobial usage was quantified as days of therapy (DOT) per 1000 patient days. Results: Common antimicrobials used in descending order of DOT were amikacin, colistin, and meropenem. Ampicillin, cefotaxime, and gentamicin were rarely found suitable for use based on the reported antibiograms. Piperacillin-tazobactam + amikacin regimen was the most commonly used empirical regimen. The case fatality rate was 4% in our study sample. Conclusion: Ampicillin, cefotaxime, and gentamicin had limited effectiveness in the majority of cases. Although there is a need of alignment with national treatment guidelines in NS, yet, the concurrent scope of periodic survey and research must be available for changeover to evidence-based local individualization of empirical antimicrobial therapy wherever required.

Keywords: Antimicrobial use, days of therapy, neonatal septicemia, neonatal intensive care unit


How to cite this article:
Das M, Pal N, Dolui SK, Choudhury S. Pattern of antimicrobial usage in neonatal septicemia at neonatal intensive care unit of a tertiary care hospital in Kolkata. J Nat Sc Biol Med 2019;10:178-83

How to cite this URL:
Das M, Pal N, Dolui SK, Choudhury S. Pattern of antimicrobial usage in neonatal septicemia at neonatal intensive care unit of a tertiary care hospital in Kolkata. J Nat Sc Biol Med [serial online] 2019 [cited 2019 Dec 7];10:178-83. Available from: http://www.jnsbm.org/text.asp?2019/10/2/178/262956




   Introduction Top


Septicemia is one of the leading causes of morbidity and mortality among neonates, particularly in the developing countries including India and identifying high-risk neonates is important.[1],[2],[3] This is a clinical syndrome characterized by systemic signs of infection, accompanied by bacteremia or fungemia in the 1st month of life. As expected, antimicrobials are the key drugs for the treatment of neonatal septicemia (NS) and also among the most commonly prescribed drugs in a neonatal intensive care unit (NICU).[4],[5] Due to paucity of specific local studies, the prescriber often extrapolates information from studies on other population.[6] Furthermore, injudicious use of antimicrobials has led to an alarming rise in antimicrobials resistance, which poses a major threat to public health worldwide.[7] National treatment guidelines for antimicrobial use in infectious diseases issued by the Government of India in 2016 steers the clinicians for prescribing antimicrobials, however, evidence of the local practice pattern is very limited.[8] Hence, periodic evaluation of antimicrobial prescribing patterns is the need of the moment to streamline and to guide the regional antimicrobial prescriptions.

An accepted metric for evaluation and quantification of antimicrobial use in pediatric population is days of therapy (DOT): the number of days that a patient is on an antimicrobial, regardless of dose. DOT is number of days patient receives antimicrobials multiplied by the number of antimicrobials administered simultaneously. For example, in a child receiving treatment for 5 days but treated with two different antimicrobials at the same time, DOT becomes ten. DOT is conventionally standardized with a denominator of 1000 patient-days.[9] In this study, we quantified and analyzed the current patterns of antimicrobial utilization in NS and noted the clinical outcome of septicemic neonates. Inferences from this study may be used to guide future antimicrobial prescriptions thereby maintaining alignment with the very idea of antibiotic stewardship.


   Materials and Methods Top


A prospective observational study was carried out in NICU in a tertiary care hospital in West Bengal, Kolkata, India, from January 2017 to June 2017. Medication records of neonates admitted to NICU for more than 24 h for confirmed or suspected septicemia were evaluated after obtaining ethical clearance from Institutional Ethics Committee and written informed consent from their guardians. Neonates who were transferred to other ward or hospital or died within 2 days of NICU stay, with congenital anomalies, cancer or with surgical complications were excluded from the study. A total of 102 consecutive eligible cases were analyzed. Septicemia was diagnosed by the clinician based on clinical symptoms namely lethargy, poor feeding, food intolerance, and signs, namely bleeding manifestation, shock, convulsion without hypoglycemia, respiratory distress, apnea, sclerema, and laboratory parameters (C-reactive protein [CRP], total leukocyte count, platelet count, toxic granules, band cells, microerythrocyte sedimentation rate, and blood culture). Data pertaining to gender, place of delivery (intramural, extramural), onset of septicemia (early onset septicemia [EOS] and late-onset septicemia [LOS]), gestational age (>37 weeks, 35–37 weeks, <35 weeks), birth weight (>2.5 kg, 1.5–2.5 kg, <1.5 kg), antimicrobial therapy-related complications, clinical outcome, and diagnosed microbial agent in culture positive cases were recorded through a predesigned case record form. All antimicrobials used from admission till the outcome was noted. Antimicrobials were administered empirically based on hospital records of previous antibiograms and thereafter therapeutic antimicrobial changes were applied according to respective culture sensitivity report or clinician's discretion in view of the patient's clinical profile. All quantitative data were analyzed by Microsoft Excel Spreadsheet, Microsoft Office 2013.


   Results Top


The study population included 69 intramural (born in our study institution) neonates and 33 extramural (born elsewhere) neonates. Fifty-nine septicemic babies had LOS. Most septicemic neonates (80) were born at <37 weeks. The proportion of preterm neonates (80) is more than term neonates (22). Most babies (86) belong to <2.5 kg birth weight group. Overall higher incidence of Gram-negative bacterial septicemia (Klebsiella spp, Burkholderia spp, Pseudomonas spp.) was observed. Fungal (Candida spp.) septicemia was predominant in babies with LOS. As expected, all the neonates received parenteral antimicrobials. The number of antimicrobials administered in a neonate ranged between 1 and 6. For example, 1 antimicrobial received by 3% neonates, 2 by 24%, 3 by 43%, 4 by 20%, 5 by 5%, and 6 by 5% neonates. Change in the initial empirical antimicrobial order remained unaltered in 24% neonates. Mean number of antimicrobials received by the neonates was 3.2 (standard deviation = 1.1). The total DOT was 4236, with a median of 39 (IQR 30–48 days). The total patient days (PD) amounted to 7236 during the study period. Hence, the total DOT/1000-patient-days was 585.41. The DOT of the most commonly used antimicrobial, i.e. amikacin was 95 DOT/1000 PD [Table 1]. In intramural neonates, colistin was the most commonly used antimicrobial closely followed by ciprofloxacin and amikacin [Table 2]. In extramural babies (referred and admitted for complication after birth to our NICU) meropenem was most commonly used followed by amikacin. Colistin was the most frequently used antibiotic in EOS group [Table 3]. In LBW neonates (1.5–<2.5 kg) and in 35–37 weeks' gestational age neonates, amikacin, ciprofloxacin, and piperacillin-tazobactam were frequently used [Figure 1]a and [Figure 1]b. Meropenem and colistin were commonly used followed by amikacin in babies weighing >2.5 kg and in term babies. Regarding very low birth weight babies and babies born at <35 weeks, the descending order of frequency of antimicrobial use was amikacin, meropenem, and piperacillin-tazobactam. Piperacillin-tazobactam + amikacin combination was the most commonly used empirical regimen [Figure 1]c. Other commonly used empirical antimicrobial regimens were meropenem + vancomycin and cefotaxime + amikacin. We observed that in 76% of cases primary empirical antimicrobials were replaced by alternative regimen(s) after receiving culture positive antibiogram reports within 3–4 days or after judging poor clinical response (over 48–72 hrs) to the empirical antimicrobial therapy. In 24% of neonates, clinical improvement and cure were observed on treatment with initial empirical antimicrobial regimen therapy. No antimicrobial associated complication such as rash, diarrhea, renal or hepatic compromise was observed in neonates under the study. Study group wise outcome is depicted in [Figure 2]. Case fatality rate (CFR) was 4% in our study population.
Table 1: Type and quantification of antimicrobials used in our study

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Table 2: Frequency of antimicrobial usage in intramural and extramural neonates

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Table 3: Frequency of antimicrobial usage in neonates with early onset septicemia and late onset septicemia

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Figure 1: (a) Frequency of antimicrobials used in gestational age study groups. (b) Frequency of antimicrobials used in birth weight groups. (c) Frequency of empirically used antimicrobial regimens

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Figure 2: Outcome of the neonates in various study groups

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   Discussion Top


The present study describes the utilization pattern of antimicrobials in a NICU of a tertiary care hospital in West Bengal, India. Data collected from 102 septicemic neonates showed that most septicemic neonates belonged to <37 weeks gestational age group similar to findings of Suryawanshi et al., Galhotra et al., and Shinde et al. as explainable by poor immune status.[10],[11],[12] On the contrary, Vaniya et al. have documented more number of term births.[13]

Most of the neonates received at least three antimicrobials (43%). The majority received 2-4 antimicrobials similar to findings of Suryawanshi et al. and Vaniya et al.[10],[13] We found that 24% neonates received two antimicrobials (two antimicrobial combinations empirical regimen) because the empirical therapy matched the antibiogram or the blood culture negative septicemic neonates clinically improved with the empirical regimen. According to Vaniya et al., 58% neonates received 4 or more antimicrobials whereas our study 30% neonates received the same.[13] Our findings suggest that substantial number of cases do not show satisfactory response with empirical antimicrobials. Few patients also received as many as 5–6 antimicrobials in our study. The causes of changing regimen were clinical deterioration or mismatch antibiograms. Rarely, no clinical improvement was noted even with antibiogram directed therapy. Amikacin, colistin, meropenem, and piperacillin-tazobactam were the most commonly used antimicrobials in descending order of utilization. Quantification of antimicrobial use in Scout study done in Texas in 2015 shows there was less use of antimicrobials as compared to ours (323 DOT/1000PD vs. 585 DOT/1000 PD).[14] Only a limited number of Indian studies have attempted to quantify antimicrobial consumption in the adult population, however, the same has not been attempted yet in neonatal population. DOT metric of our study confirmed the highest use of amikacin closely followed by colistin and meropenem. Amikacin was used in combination therapy along with variable bactericidal antimicrobials and also was reported sensitive in most antibiograms. Piperacillin-tazobactam with amikacin was the most commonly used empirical regimen in our study. In a recent literature, amikacin was reported as the most frequently used antimicrobial similar to our study.[13] Gentamycin and ampicillin were most commonly used antimicrobial agents in Scout study.[14] Blood culture proven NS mostly caused by multidrug-resistant (MDR) Gram-negative bacilli demanded the use of these otherwise reserve antimicrobials namely colistin and meropenem. Recent researches have proven the efficacy of colistin in the treatment of NS despite being a highly toxic drug.[15],[16] Colistin was also used in highly morbid neonates in culture-negative septicemia. Gram-positive cocci (GPC) were less commonly demonstrated to cause NS in our study and MDR is also less prevalent in GPC. This probably explains less use of vancomycin and rare administration of linezolid. This microbial heterogenicity further emphasizes that empiric antimicrobial treatment may justifiably vary at times among different locations.[5]

Similar to our study more use of piperacillin tazobactam, meropenem, vancomycin, amikacin have been reported in extramural neonates (to give wide antibacterial coverage) compared to intramural cases by Suryawanshi et al.[10] Shinde et al. have noted common use of ampicillin and cefotaxime in all gestational age groups.[12] In contrast, we observed extensive use of meropenem and colistin. In our study population, in addition to amikacin, ciprofloxacin has been used very commonly in premature neonates, whereas meropenem and colistin were noted to be more commonly used in term neonates. On the contrary, Suryawanshi et al. documented the use of colistin in grossly preterm babies. They also mentioned higher use of levofloxacin, piperacillin-tazobactam, and meropenem in preterm and common use of amikacin and cefotaxime in term infants.[5] Antifungal use in LOS following culture confirmed fungal septicemia outbreak was observed in the initial phase of the study in 29% cases. Prompt and aggressive use of antifungals is justified in a clinically septic neonate having neutropenia and raised serum CRP, who do not respond satisfactorily to antibiotics.[17]

The most common choice of piperacillin tazobactum + amikacin combination as empirical regimen in our study population was based on previous institutional antibiogram records of culture-proven NS and the outcome of the neonates. Majority of the past studies highlight Escherichia coli and Group B Streptococcus as common isolates from septicemia case.[18] However, during the study, nearly half of the reported pathogens were other multidrug-resistant bacteria, for example, Klebsiella spp., Burkholderia spp. (well known for its intrinsic resistance to many antimicrobials including colistin), Pseudomonas spp., Methicillin-resistant Staphylococcus aureus, etc., and the same was noted in recent and past records of our NICU. Piperacillin-tazobactam seems effective antimicrobial for many of the above bacterial agents and when used in combination with amikacin serves to prevent the emergence of antimicrobial resistance and hence justifies for favored empirical antimicrobial in our setup. Ampicillin + aminoglycoside combination and third-generation ceplalosporin + aminoglycoside combination has been reported as commonly used empirical therapy of NS in many past researches.[8],[10],[12] In only 13% of our study population, this empirical choice has been followed. Our national guideline states that in asymptomatic babies at high risk of sepsis, for example, foul-smelling liquor or two or more risk factors warrants the initiation of antibiotic therapy with ampicillin + gentamicin. In cases with severe sepsis (Sclerema/shock/suspicion of meningitis) cefotaxime + amikacin is recommended. If sepsis is suspected to be health-care associated or if there is no response in 48–72 h of initial therapy or if there is documented resistance then change to injection piperacillin-tazobactam + amikacin. Vancomycin can be added to the regime if staphylococcus is suspected.[8] Quite unexpectedly, we hardly came across any blood culture isolate sensitive to ampicillin, cefotaxime, and gentamicin. In accordance to a higher incidence of Gram-negative bacterial septicemia detected in our study meropenem was used as initial antimicrobial in very sick neonates and also as a therapeutic change deduced from antibiogram reports showing resistance to all other beta-lactam antimicrobials and fluoroquinolones. However, in moribund neonates (19%) presenting with shock, respiratory distress, convulsion, altered sensorium, and sclerema the clinician primarily used colistin + ciprofloxacin combination. Otherwise, colistin was mostly used in carbapenem-resistant organisms after obtaining antibiogram. Vancomycin was used maximally in >2.5 kg birth weight group. A limited number of studies have reported vancomycin use in various birth weight groups of septicemic neonates. Following the outbreak of culture-confirmed fungal septicemia, in two neonates antifungal (fluconazole) therapy was empirically started ensuing favorable outcome. As recommended by Sivanandan et al. we also believe that in developing countries, empiric antimicrobial therapy might be individualized for each hospital or region.[19]

The outcome of the neonates was classified into complete recovery without sequel, recovery with immediate sequel (viz., hydrocephalus and bronchopulmonary dysplasia), death and leave against medical advice. We noted an overall CFR of 4% among studied septicemic neonates, which is comparable to the documentation of Vaniya et al., i.e. 5.75%, and far less than report of Suryawanshi et al., i.e. 15.4% and Shinde et al. (10%).[10],[12],[13] Total 81% neonates recovered without sequel, and 11% neonates recovered with sequel. Good survival without sequel was noted in (90%) in <35 weeks as comparable to Shinde et al. They also mentioned gestational age group specific mortality such as 24–27 weeks: 40% mortality, 28–30 weeks: 32%.[12] However, we found only CFR of 8% in <35-week group. We found the highest recovery in <35 weeks and least recovery in >37 weeks group. We lost no neonate from EOS whereas 7% neonates died from LOS group. Kamble and Ovhal state that mortality in EOS: 29.6% and LOS: 12.06%.[20] CFR of 17% and 10% in EOS and LOS, respectively, has been documented in a similar recent Indian study mentioning cefotaxime or ampicillin + aminoglycoside as preferred empirical therapy in NS.[21] Since in our study patients were well monitored for drug-associated adverse effects and there was no such observable antimicrobial associated complication, so this emphasizes overall safety and tolerability of our regimens. We also infer that the low case fatality in our study population reinforces the effectiveness and safety of antimicrobial therapy used in our setting.

Limitation of the study

This is a short-term study with small sample size. We suggest that a study on a large sample size over a longer period might be able to infer the results with a higher level of confidence.


   Conclusion Top


In the present scenario, it is difficult to stringently align with previously documented traditional antimicrobial use patterns. We noted the administration of multiple antimicrobials previously less frequently used in NS (meropenem, colistin, and fluconazole). This is not attributable to lack of clinician's awareness regarding national guideline, rather, it reflects reported antibiograms and clinical status of the patient. We emphasize that the empiric piperacillin-tazobactam + amikacin regimen resulted in favorable outcome in our setup. Reports from multiple centers may be pooled to re-strengthen or modify the existing national guideline. We recommend colistin and vancomycin to be kept aside as reserve antimicrobials for use in dire and or essential circumstances. Effects of the use of colistin and vancomycin should be studied specifically in neonates. Inappropriate empirical antimicrobial therapy promotes the use of multiple antimicrobials and sequential prescription changes for the treatment of nonresponding patients, henceforth resulting in prolonged hospitalization and substantial economic loss.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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