tackling multidrug resistance in neonatal sepsis: a south asia … · 2019-02-06 · confidential:...

Confidential: For Review Only

Tackling Multidrug Resistance in Neonatal Sepsis: A South

Asia Perspective

Journal: BMJ

Manuscript ID BMJ.2018.045301

Article Type: Analysis

BMJ Journal: BMJ

Date Submitted by the Author: 31-May-2018

Complete List of Authors: Chaurasia, Suman; All India Institue of Medical Sciences, Pediatrics Sivanandan, Sindhu; All India Institue of Medical Sciences, Pediatrics Sankar, M Jeeva; All India Institute of Medical Sciences , Pediatrics Ellis, Sally; Drugs for Neglected Diseases initiative, Global Antibiotic R&D Partnership

sharland, mike; St. Georges University London, Pediatric Infectious Disease Research Group Agarwal, Ramesh; All India Institute of Medical Sciences, Pediatrics

Keywords: Neonatal Sepsis Multidrug Resistance South Asia Early-onset Late-onset

https://mc.manuscriptcentral.com/bmj

BMJ


Title Tackling Multidrug Resistance in Neonatal Sepsis: A South Asia

Perspective

Authors’ names Suman Chaurasia, Sindhu Sivanandan, M Jeeva Sankar, Sally Ellis,

Mike Sharland, Ramesh Agarwal

Address for each

Author

Authors’ names and

position

1. Suman Chaurasia, Consultant/PhD Fellow, Department of

Pediatrics, All India Institute of Medical Sciences, New Delhi

2. Sindhu Sivanandan, Ex-Senior Resident, Department of


3. M Jeeva Sankar, Assistant Professor, Department of


4. Sally Ellis, Neonatal Sepsis Project Leader, Global Antibiotic

R&D Partnership (GARDP), c/o Drugs for Neglected Diseases

initiative (DNDi), Geneva

5. Mike Sharland, Paediatric Infectious Diseases Research

Group, St George's University London

6. Ramesh Agarwal, Professor, Department of Pediatrics, All

India Institute of Medical Sciences, New Delhi

Corresponding

Author

Dr Ramesh Agarwal

Professor, Department of Pediatrics,

WHO Collaborating Centre for Training & Research in Newborn

Care

All India Institute of Medical Sciences, Ansari Nagar, New Delhi

110029

Tel 91-11-2654 6167

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Title: Tackling Multidrug Resistance in Neonatal Sepsis: A South Asia Perspective

Standfirst: Sepsis caused by multidrug resistant pathogens has emerged as a major threat to

neonatal survival and well-being in South Asia and carries serious global implications. Suman

Chaurasia and colleagues present a situational analysis, and discuss the issues and the way

forward.

Abstract

Sepsis continues to be the third most common cause of deaths among the neonates across the

world. Most of these deaths occur in developing countries settings, with South Asia region alone

accounting for around 40% of global burden. Recent regional trends indicate soaring

antimicrobial resistance among the causative organisms- a major threat to neonatal survival and

well-being in South Asia with potential global implications. We conducted a systematic review

to perform a situational analysis and discuss the way forward.

The systematic review highlighted similar rates of culture-positive sepsis still persisting over the

decades, compounded by the recent alarming presence of multidrug resistant organisms

(MDROs) in the region. Pertinent questions that emerged were probed with the aid of Delhi

Neonatal Infection Study (DeNIS) collaboration’s database and led to a three-pronged critical

approach, overlapping with existing (inter)national recommendations. Setting up a diagnostic-

focussed antibiotic stewardship mass movement will aid in slowing the evolution of MDROs;

elucidating transmission pathways will prevent exposure/infection due to the latter; and

establishing a regional dedicated clinical drug trial network in collaboration with multiple

stakeholders will potentially ensure alternative treatment options against MDRO caused sepsis.

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Key Messages

• The incidence of sepsis in neonates in South Asia region has remained unchanged but the

proportion of sepsis caused by multidrug resistant organisms (MDROs) has risen sharply

potentially leading to higher mortality burden

• This calls for concerted efforts to slow the evolution of MDROs by strengthening

antibiotic stewardship in health facilities alongside devising effective point-of-care

diagnostics; preventing the MDRO-infections by first understanding and then interrupting

their transmission pathways; and finding effective drugs and adjuvant care modalities by

building dedicated regional clinical trials network

Word count: 2278/2200

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Introduction

Systemic infection or sepsis in the neonatal period – the first 28 days of life – is the third most

common cause of deaths among neonates around the world.1 Neonatal sepsis includes

bloodstream infection, meningitis, and pneumonia. It is usually categorized into ‘early-onset’

sepsis (EOS; onset within 72h of birth) and ‘late-onset’ sepsis (LOS; onset beyond 72h). The

former is considered to be caused by pathogens vertically transmitted from mother while the

latter is due to pathogens acquired horizontally from environment and/or caregivers. Sepsis is

also classified as culture-positive or culture-negative depending upon isolation of pathogen(s)

from blood or other sterile fluids. Of the global burden of sepsis-related neonatal deaths, nearly

40% occur in resource-limited countries of South Asia (SA: Afghanistan, Bangladesh, Bhutan,

India, Maldives, Nepal, Pakistan, and Sri Lanka).1

Neonates as immunocompromised hosts are more prone to infections. Thus, antibiotics are

among the commonest drugs to be used in NICUs.2 The resultant antibiotic selection pressure

leads to development of antimicrobial resistance (AMR).3 Recent reports indicate an alarming

level of multidrug resistance (MDR) among common pathogens of neonatal sepsis in the region.4

5 Every year, around 56500 neonatal deaths are attributable to sepsis caused by pathogens

resistant to first-line drugs in India alone.6 Resistance elements like CTX-M-15 and NDM-1

genes may have disseminated globally after originating from SA.7 8 In this article, we discuss

AMR patterns in neonatal sepsis in SA, contextual issues and perspectives.

Neonatal sepsis in South Asia

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Confidential: For Review OnlyWe conducted a systematic review of literature published in PubMed between January 2000 and

April 2018 using search terms (newborn OR neonate) AND (sepsis OR infection OR antibiotic

OR antimicrobial) (Supplementary Panel 1). After filtering for countries in SA, the search

strategy yielded a total of 2536 studies. Among the 105 studies finally identified (India=68;

Pakistan=15; Bangladesh=7; and Nepal=14), we found more than one unique cohorts/epochs

datasets within the studies and treated them separately, making a total of 114 reports. We also

performed secondary analysis from our Delhi Neonatal Infection Study (DeNIS) database, as and

when necessary.9

Incidence and onset of neonatal sepsis

The incidence of culture-positive sepsis was 17.8 per 1000 live births (95% CI 14.3-21.2, n=17

reports; Table 1). In community settings, it was lower - varying from 2.910 to 6.711 per 1000 live-

births. The incidence of culture-positive sepsis in SA hardly changed from that in 2005 (15 per

1000 live-births),5 and remained 3-4 fold higher than that (1-5 per 1000 live-births) reported in

high income countries (HICs).5 EOS constituted around two-thirds (62.3 %; 61.4-63.0) of total

sepsis.

Pathogen profile and antimicrobial resistance pattern

Among all isolates (n=24,273) from SA region, Gram-negative organisms (63%) were the most

common pathogens, with Klebsiella spp. (22.3%), Escherichia coli (13.9%) and Acinetobacter

spp. (7.9%) being the top three. The common Gram-positive organisms were Staphylococcus

aureus (19.9% of total isolates) and coagulase negative staphylococci (8.5%). There was a

striking similarity between the pathogen profile of EOS and LOS.

Overall, the common organisms were Klebsiella spp., Staphylococcus aureus, Escherichia coli,

and Acinetobacter spp., and they uniformly exhibited high degree of resistance to WHO

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Confidential: For Review Onlyrecommended first-line drugs namely, ampicillin (weighted median 69% to 88.2%) and

gentamicin (54.5% to 75.3%), as well as third generation cephalosporins like cefotaxime (51.2%

to 72.5%) (Table 2).12 13 However, most Gram-negative isolates were susceptible to WHO-

classified ‘Watch Group’ antibiotics like meropenem (carbapenems), colistin, and tigecycline

(Supplementary Table 1).14 About a half (weighted proportion 46.5% [41.9-51.1]) of

Staphylococcus aureus isolates were methicillin resistant (MRSA) but most remained susceptible

to WHO-classified ‘Watch Group’ as vancomycin and linezolid.14

Available AMR rates against first-line antibiotics (ampicillin: 81%-82%; gentamicin: 55-74%)

and cefotaxime (51%-54%) of Klebsiella spp and E. coli indicate the pattern seemed to have

remained almost unchanged over the decade.5 A recent systematic review from India reported

similar AMR rates among Gram-negative organisms.15

Multidrug resistance amongst pathogens

The limited number of publications and heterogeneity in definitions of MDR made it challenging

to draw inferences (Supplementary Table 2). The most common used definition for MDR was

resistance to 2-3 or more antimicrobial agents/classes, usually involving first-line and sometimes

second-line drugs. An experts panel defined extreme-drug-resistance (XDR) as resistance to all

categories but one or two antibiotics tested.16 Recent reports used presence of extended spectrum

beta-lactamase (ESBL- a key enzyme inducing MDR) in the pathogens as a surrogate for MDR.6

MDR rates in Klebsiella spp., Escherichia coli and Acinetobacter spp. (3-4 reports for each)

were 70.7% (95% CI 66.1-75.3), 54.0% (48.1-59.9), and 78.7% (73.9-83.4), respectively (Table

2). Notably, all these studies were published in the last five years. The ESBL rates among

Klebsiella spp., Escherichia coli and Acinetobacter spp. were 53.8% (95% CI 50.9- 56.6, n= 25),

42.4% (38.6-46.2, n= 18) and 65.6% (55.9-75.3, n=3) respectively (Table 1). Of the studies

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Confidential: For Review Onlyreporting XDR (n=3-4 for each), rates were 5.2% (95% CI 2.5-7.8) in Klebsiella spp. 2.9% (0.7-

5.2) in E. coli and 17.5% (13.1-21.9) in Acinetobacter spp.

Comparing EOS with LOS (n=3), MDR rates in EOS and LOS were similar amongst Klebsiella

spp., E. coli and Acinetobacter spp. (Table 2). However, in the study that provided most isolates

and more robust data, the MDR rate was higher in EOS by nearly 10 percentage points (in top

two pathogens- Klebsiella spp. and E. coli ).9

Among Gram-positive organisms, about half of S aureus isolates labelled methicillin resistance

(see above) are generally equated to MDR. A recent systematic review also noted that 50% of S

aureus isolates were methicillin-resistant.15

Case fatality rates

The median case fatality rate (proportion of deaths attributable to sepsis among cases of sepsis;

CFR) for culture-positive sepsis was 34.4% (IQR 33.1 to 35.6, n= 19; Table 1). It was higher for

EOS than LOS; 45.4% (42.2 to 48.6, n= 9) vs. 26.4 % (23.6 to 29.2, n= 6).

The median CFR among the three commonest Gram-negative MDR pathogens was slightly

higher than non-MDR counterparts: 59.8% (95% CI 54.5 to 65.2) vs. 55.8% (49.1 to 62.6). It

was nearly double for ESBL-producing pathogens than for non-ESBL-producers (27.3% vs.

15.6%).

Key findings and inferences regarding sepsis in South Asia

The incidence and case fatality of culture-positive sepsis continues to be high in SA. The

bacterial pathogen profile is similar across the region with a predominance of MDR organisms

(MDROs). EOS comprises of two thirds of all cases, with its pathogen profile resembling that of

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Confidential: For Review Onlyclassical LOS. Given its larger share and higher case fatality rates than LOS, EOS carries a

greater epidemiological significance in SA.

High degree of MDR with evidence suggesting its recent emergence in the region is quite

alarming. In contrast to LOS, MDR in EOS is greater and associated with high CFR. The

remarkable degree of resistance exhibited by the pathogens to most antibiotics leaves clinicians

grappling for treatment options.

Knowledge gaps, insights/analyses from DeNIS and perspectives

With this recap, several pertinent gaps in knowledge seek our attention:

1. What is the reason behind recent emergence of MDRO and how can we mitigate the

evolution of MDRO?

2. What are the source and routes of transmission of MDROs in EOS so as to guide

effective preventive strategies?

3. Lastly, do existing regimens still hold value to treat infection due to MDROs? And, how

best new or alternative treatment options can be devised in LMICs?

We probed the DeNIS database to better understand the issues and navigate the way forward. For

the purpose of this article, we limited the scope of discussion to these burning questions.

I. Mitigating evolution of MDR organisms by enhanced antibiotic stewardship: The evolution

of MDRO in SA is likely to be multi-factorial. Here widespread antibiotic residues generated

from agriculture and pharmaceutical industries have generally contaminated the environment,

including that of health sector (Panel 1).16 Additionally, prescribing antibiotics for sick

neonates in facilities carries inherent complexities. Since initial clinical features of sepsis are

non-specific and underlying CFR is high, the treating physicians invariably end up initiating

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Confidential: For Review Onlyempiric broad-spectrum antibiotics in neonates whenever confronted with sickness.5

Consequently, susceptible organisms in neonatal surroundings face multi-dimensional

selection pressure to evolve as MDROs.17

Since environmental factors are outside the purview of the current article, we examined the

antibiotic prescription rates in DeNIS study. Of all neonates suspected to have sepsis and

initiated on antibiotics, a quarter of them was finally proved not to have sepsis at all and

another quarter had culture-negative sepsis (Panel 2, Item 1a). So, antibiotics could have

been potentially stopped early (in ‘no sepsis’ cases) or given for a shorter duration (in

culture-negative cases) in at least half of the neonates. A point-of-care reliable biomarker can

effectively guide antibiotic prescription and in turn, address high selection pressure. Such

use of diagnostic modalities is now integral to structure of antibiotic stewardship program

(ASP) - a multi-intervention tool to achieve rationalized antibiotic usage.18

In this context, some upcoming biomarkers like procalcitonin can guide both initiation and

early discontinuation of antibiotics.19 20 However, robust evidence for diagnostic accuracy

and cost-effectiveness of biomarkers for neonatal sepsis are generally lacking in LMICs.

Besides curtailing antibiotic consumption effectively,21 22 ASP has now demonstrated

reduction in emergence of MDR Gram-negative organisms in hospitals, by as much as 51%

in HICs, with synergistic benefits of simultaneous infection prevention and control (IPC)

measures especially hand hygiene.23 However, challenges in LMICs for implementing an

effective ASP are manifold besides lack of such evidence base.24 Among the major barriers

are, the fixed beliefs and attitudes of the care-providers- requiring integration of behavioural

change approaches in the implementation since the outset.18 More importantly, objective

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Confidential: For Review Onlyuniform benchmarking outcome for ASP-based audits (such as C. difficile reduction rates

used in HICs) is lacking.23 Therefore, there is an urgent need to address the issues around

diagnosis and implementation of ASP to slow MDROs fostering in SA.

II. Determining transmission dynamics (particularly for EOS) to prevent MDROs’

exposure/infection: In HICs, a clear evidence that Group B streptococci, the predominant

pathogen in EOS, get vertically transmitted from colonized mothers to their neonates

culminated into instituting intrapartum antibiotics prophylaxis to high risk mothers.

Consequently, this strategy led to a major reduction in EOS in HICs.25 Despite the

dominance of EOS in SA, the transmission dynamics of pathogens- increasingly MDROs-

remain unresolved.

The current review underscored EOS pathogen profile bore resemblance to classical

healthcare (LOS) associated pathogens suggesting horizontal transmission. We found no

variation in the pathogen profiles in 12h and 24h time epochs after birth until discharge in

DeNIS collaboration study. On the other hand, a quarter of culture-positive sepsis was

diagnosed by 24h of birth, with nearly 10% occurring before 12h (Panel 2, Item 1b),

potentially too short time for manifesting EOS by horizontal transmission (through

colonization and then invasion). Given that EOS manifested so early, and was associated

with high degree of MDR as well as case fatality, primary prevention seems to be the logical

intervention of choice. But, to enable preventive strategy, the following crucial questions call

for urgent answers: do the MDROs colonize the maternal genital tract and consequently are

vertically transmitted to their babies during delivery? Or is there simply an ‘ultra-early’

horizontal transmission occurring in birthing rooms and NICUs? Or, a mix of both? Studies

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Confidential: For Review Onlyaddressing this issue in LMIC are scanty- mostly involving phenotypic correlation of

colonizing and invasive isolates.26 27 Hence, high quality concordance studies- integrating

metagenomic with conventional approaches-28 are essential to elucidate the transmission

pathways and devise optimum preventive strategies.

III. Improving clinical management of MDR sepsis: Using DeNIS database, we compared CFRs

of culture-positive sepsis amongst neonates whether or not clinicians upgraded antibiotics

from first-line (defined according to prevailing practices across participating units: amikacin

or ciprofloxacin or ceftriaxone or piperacillin-tazobactam) after at least 48h of therapy to

second-line (vancomycin or meropenem or cefoperazone+sulbactam). We classified these

neonates into three categories: (i) when first-line antibiotics alone covered the isolated

pathogen (‘concordant’ group); (ii) when first- did not but second-line covered the pathogen

(‘partially discordant’) and (iii) when neither first- nor second-line antibiotics covered the

pathogen (‘fully discordant’). We observed a serially increasing order of CFR from first to

third categories (23.9%, 31.6% and 57.3% respectively; Panel 2, Item 1c), even in EOS. The

fact that worst outcome is associated with fully discordant group, clearly underscores right

choices of antibiotics are vital.

In this context, novel antibiotics, active against carbapenem-resistant organisms, such as

plazomicin and ceftazidime/avibactam are on the horizon; but, currently high costs (of

around $100/day) preclude their use in LMICs.29 Recycling of older drugs such as colistin or

polymixin B or tigecycline have been explored and proved life-saving in our settings.

However, barring reports of off-label usage, hardly any pharmacokinetic or

pharmacodynamic data of these drugs are available to guide dosing decisions in neonates.30

Global Antibiotic Research & Development Partnership (GARDP) and Pediatric trial

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Confidential: For Review Onlynetwork are few organizations working in this priority area.31 32 Largely, there is an

overarching need to develop a committed paediatric/neonatal clinical trials platform in the

region evaluating range of interventions including novel, older off-patent or combination

antibiotics, and supportive care, besides IPC measures.33 This platform, along with the

proposed three-dimensional strategy, would indeed act as complementary to comprehensive

AMR surveillance, and other supplementary modalities suggested in various national and

global action plans.34-36

Conclusions

Our article highlights the virtually unchanged sepsis patterns over the decades and steadily

increasing multidrug resistance among neonates in South Asia. We present analyses and insights,

and a promising blueprint towards curbing the menace: implementing effective antibiotic

stewardship campaign with focus on point-of-care diagnostics to slow MDROs’ evolution;

understanding and attacking transmission pathways of early-onset sepsis to prevent it; and

establishing a dedicated clinical trials network employing regional data to find best suited

treatment alternatives for LMICs. This three-pronged strategy calls for concerted efforts of

multiple stakeholders to jointly engage in collaborative research and multiple strategic trials for

informing future initiatives and policy-framing.

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Confidential: For Review OnlyContributors and sources The authors work in academic institutions of India (AIIMS, New

Delhi) and the UK (SGU London), and non-profit organization (DNDi), and are engaged in

collaborative research for prevention and management of sepsis in neonates.

SC, MJS and RA conceived the idea of the paper with inputs from MS, SS and SE. SS

conducted the literature search, and extracted the data for systematic review with help from

SC. SC wrote the first draft of the manuscript. All the authors contributed to writing/editing

various sections, critically reviewing the results, finalizing the draft, and approved the final

manuscript. RA is the guarantor of the manuscript. We wish to acknowledge Mr C P Yadav,

Scientist B (Bio-Statistics), National Institute of Malaria Research (NIMR), Delhi for

assistance in statistical analysis involving DeNIS database.

Competing Interests All authors have read and understood the The BMJ policy and declare

no conflicts of interest.

Provenance and peer review Commissioned; externally peer reviewed.

This article is one of the South Asia series commissioned by The BMJ based on the

collaboration of Drugs for Neglected Diseases initiative (DNDi) . The BMJ retained full

editorial control over external peer review, editing, and publication. Open access fees are

funded by the DNDi, Geneva.

Suman Chaurasia, consultant/PhD fellow1

Sindhu Sivanandan, Ex-Senior Resident1

M Jeeva Sankar, Assistant Professor1

Sally Ellis, Neonatal Sepsis Project Leader2

Mike Sharland, Professor3

Ramesh Agarwal, Professor1

1Department of Pediatrics, All India Institute of Medical Sciences, New Delhi 2Global Antibiotic R&D Partnership (GARDP), c/o Drugs for Neglected Diseases initiative (DNDi), Geneva 3Paediatric Infectious Diseases Research Group, St George's University London

Licence

“The Corresponding Author has the right to grant on behalf of all authors and does grant on behalf of all authors, an exclusive licence (or non exclusive for government employees) on a worldwide basis to the BMJ Publishing Group Ltd ("BMJ"), and its Licensees to permit this article (if accepted) to be published in The BMJ's editions and any other BMJ products and to exploit all subsidiary rights, as set out in our licence.”

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Table 1 Incidence, case fatality rates and ESBL rates of nosocomial sepsis: country specific

Countries

(no. of studies, no. of isolates)

India

(n=68, 18640)

Pakistan

(n= 15, 3557)

Bangladesh

(n=7, 584)

Nepal

(n=14, 1331)

Overall SA

(n= 105#, 24,112 )

Incidence of culture positive sepsis, per

1000 live births

17.8 (14.3-

21.3); 16

NA NA 11.6; 1 17.8 (14.3-21.3); 17

CFR: culture positive sepsis 34.4%

(33-35.7); 14

30.9%

(25.7-36.2); 2

19.1%

(11.7-26.5); 2

64.7%

(54.3-75); 1

34.4%

(33.1-35.6); 19

CFR: EOS 37.8%

(32.7-42.9); 3

39.1%

(33.9-44.3); 3

66.7%

(49.8-83.5); 1

73.8%

(66.6-81); 2

45.4%

(42.2-48.6); 9

CFR: LOS 13.5%

(8.3-18.6); 2*

14.9%

(11-18.7); 2

22%

(7.1-36.8); 1

13.3%

(3.9-22.6); 1

26.4 %

(23.6-29.3); 6

ESBL rates

(Pooled estimates with 95% CI); N

·Klebsiella spp.

·E. coli

·Acinetobacter spp.

53.6%

(50.7-56.5); 21

NA

NA*

33%

(3-63); 1

53.3%

(50.4-56.2); 22

42.2%

(38.5-46); 16

NA NA 50%

(1-98); 1

42.2%

(38.6-46.2); 17

65.6

(55.9-75.3); 3

NA

NA NA 65.6

(55.9-75.3); 3

MR-Staphylococcus aureus (MRSA)

(Pooled estimates with 95% CI); N

43.2%

(39.9-46.5); 17

61%

(49.1-72.8); 1

NA

26%

(12.8-39.3); 3

43.3%

(40.2-46.5); 21

Data represents weighted median (95%CI), N= no. of studies, unless stated otherwise. *Community-based studies (n=3) were not

included in the results in this table; *removed outliers for these data-points. SA, South Asia; CFR, case fatality rate; EOS, early

onset sepsis; LOS, late onset sepsis; ESBL, extended spectrum beta-lactamase; MR, methicillin resistant; NA, not available.

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Table 2: Pathogen specific CFR and AMR pattern

Pathogen (# of isolates)

Ampicillin

Gentamicin 3rd gen. cephalosporins Meropenem/

Methicillin

MDR XDR EOS LOS

Cefotaxime Ceftazidime

Klebsiella spp.

(total n= 4312)

86.8%

(85.8-87.3);

2806

75.3% (74-

76.7); 2954

72.5%

(71.3-73.7);

4126

74.5% (73-

75.9); 2455

10.4% (9.4-

11.5); 2540

70.7%

(66.1-75.3)

5.2%

(2.5-7.8)

69.3%

(59.8-78.8)

70.9%

(65.0-77.0)

Escherichia coli

(n= 2798)

88.2% (87-

89.5); 2196

67.9% (66-

69.8); 2254

66.9%

(65.3-68.6);

2745

69.4% (67.4-

71.4); 1773

8.1% (6.8-9.4);

1551

54.0 %

(48.1-59.9)

2.9%

(0.7-5.2)

45.24%

(35.5-54.9)

49.3%

(39.9-58.6)

Acinetobacter spp.

(n=1347)

86.2%

(83.8-88.5);

633

68.1% (65.1-

71); 792

80.3%

(78.2-82.4);

1121

73.6% (70.8-

76.3); 718

64.8% (62.2-

67.4); 828

78.7%

(73.9-83.4)

17.5%

(13.1-21.9)

81.4%

(75.5-87.4)

83.0%

(74.7-91.4)

Staph. aureus (n=2437) 69% (67.3-

70.6);2266

54.5% (52.4-

56.6); 1773

51.2% (49-

53.3);1753

NA 46.5% (41.9-

51.1); 310

NA NA 39.2%

(28.0-50.4)

40.3%

(28.5-52.2)

Data represents weighted median (95%CI), N= no. of isolates tested, unless stated otherwise. MDR, multidrug resistance; XDR, extreme drug resistance; EOS, Early onset sepsis;

LOS, late onset sepsis; NA, Not applicable.

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Panel 1: Schematic diagram to describe the evolution and spread of pathogens into multidrug resistant

organisms (MDROs), and its exposure leading to sepsis (especially early-onset). The three arrows in red with

yellow outline and numbered 1-3 are the points our three-pronged approach highlights: 1- diagnostic-based

antibiotic stewardship program (ASP) to slow MDRO evolution, 2- decipher transmission dynamics to tackle spread

with target of primary prevention and 3- devise/facilitate newer treatment options through collaborative clinical

trials platform. IPC: Infection Prevention and Control; MDRO: Multidrug resistant organisms, NICU: neonatal

intensive care unit. NB: The pictures in the diagram have been inserted from internet resources and are indicative

only; if accepted, we shall replace them with our own hand-drawn similar sketches.

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Panel 2: Insights from DeNIS collaboration study with relevance to contextual issues in neonatal sepsis in

South Asia. * ciprofloxacin or cloxacillin or ceftriaxone or amikacin or piperacillin-tazobactam; # vancomycin

or meropenem or cefoperazone+sulbactam; NB: neonates analyzed had received at least two days’ therapy of

the first-line or second-line options.

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Confidential: For Review OnlyReferences to main text

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31. Folgori L, Ellis SJ, Bielicki JA, et al. Tackling antimicrobial resistance in neonatal sepsis. Lancet Glob

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32. Pediatric Trials Network. [Available from: https://pediatrictrials.org/ accessed 25/5/2018].

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34. World Health Organization (WHO).Antimicrobial resistance: Draft global action plan on antimicrobial

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Tackling Multidrug Resistance in Neonatal Sepsis: A South Asia Perspective

Supplementary File

Supplementary Panel 1 Systematic review: Search strategy, selection criteria and flow

diagram

Search strategy and selection criteria

Systematic search was conducted using PubMed as the primary database with the search terms; (((newborn OR

neonate) AND (sepsis OR infection OR antibiotic OR antimicrobial))) in English language between January 1,

2000 to April 2018, last search done on 27th April 2018. The results were filtered for South Asian (SA)

Countries namely; (((Afghanistan) OR (Bangladesh) OR (Bhutan) OR (India) OR (Maldives) OR (Nepal) OR

(Pakistan) OR (Sri Lanka))). Relevant articles for Nepal and Bangladesh were also searched in the website:

https://www.nepjol.info/index.php/JNPS and https://www.banglajol.info/index.php/index. The abstracts and

titles were compiled in EndNote (Thomson Reuters) and reviewed to identify relevant studies. Bibliography of

full text articles and published systematic reviews were searched to identify additional articles.

Inclusion criteria

● From a country listed in SA region

● Reports data on neonates (age 0-28 days)

● Reports on blood/sterile fluid culture positive sepsis (with or without pneumonia, meningitis or

infection at other body sites) with profile of bacterial isolates and (or) antimicrobial resistance (AMR)

data

● Reports on the total number of blood cultures obtained and the total number of pathogenic isolates and

or AMR data

● Reports should involve recognized standard for the interpretation of antibiotic susceptibility testing like

Clinical and Laboratory Standards Institute or British Society for Antimicrobial Chemotherapy or other

recognized standard.

Exclusion criteria

● Studies reporting on bacterial isolates retrieved from body surface or other body fluids including urine

in neonates without clinical evidence of sepsis or bacteraemia.

● Studies where data specific to neonatal period (0-28 days) could not be extracted

● Studies with less than 15 bacterial isolates

● Studies reporting an outbreak or an epidemic

● Studies whose full text could not be retrieved

● Studies with ambiguous or difficult to extract AMR data

Definitions used:

● Neonates: Age between 0-28 days of life

● Culture positive sepsis: isolation of pathogenic bacteria from blood or other sterile body fluids in a

neonate with presumed sepsis with or without features of pneumonia or meningitis.

● Culture negative sepsis: Neonates with clinical features of sepsis but without bacteriological

confirmation and receive a course of antibiotics for treatment

● Antimicrobial resistance (AMR): Antimicrobial resistance was defined as resistance of isolated

pathogenic bacteria to a particular antibiotic using a standardized antimicrobial susceptibility-testing

model such as the agar diffusion test or standardized method for determining the zone of inhibition or

minimum inhibitory concentration (MIC) of the isolate; ‘Intermediate’ results if available were clubbed

with ‘Resistant’.

● Early and late onset sepsis were defined as per the author’s classification based on either 72 hour cut

off or 7 day cut off.

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● Multidrug resistance (MDR) was defined as per the classification or definition used by the study

author.

● Extremely-drug-resistant (XDR) was defined resistance to all but one or two antibiotics tested.

Data extraction: Data extraction was performed by a single author (SS) using Microsoft Excel 2007

spreadsheet specifically designed for this review that collected information on author, year of study, location,

country, study setting, population, incidence of culture positive sepsis, culture positivity rate, number and profile

of bacterial pathogens isolated, sepsis related mortality, case fatality rate and antimicrobial resistance pattern.

Data extraction was cross-checked for ten percent studies by another author (SC).

Statistical Analysis

Reports on incidence, case-fatality rates and bacterial profile of neonatal sepsis were segregated based on

whether the study was conducted (or included neonates born) in the community or hospital. When the data

included both, the study was analysed under hospital based data. The pooled results were weighted for the

number of live births for incidence data and for the number of positive bacterial cultures for bacteriological

profile. The case-fatality rates for individual bacteria were weighted for the number of bacterial isolates reported

in the study for that pathogen. For antimicrobial resistance pattern, the number of isolates and the percentage of

resistance of individual bacterial isolates to various antibiotics were extracted. We calculated the median and

95% CI of AMR weighted by total sample size of blood cultures.

Results: The electronic search in PubMed database (latest search on April 27, 2018) identified 2577 articles and

an additional 19 articles were identified from reference search of articles identified from PubMed (Figure 1).

After excluding 60 duplicate reports, 2536 articles were searched using their title and abstracts. A total of 2370

records were excluded mostly because they included non-bacterial infection or included studies done in older

children. One hundred and ninety nine full text articles were reviewed and 94 excluded for various reasons.

Finally 105 studies were included. Among these, the Young Infant Clinical Study group1 provided data for 3

countries, India, Pakistan and Bangladesh on pathogen profile. Five other studies2-6

provided data separately for

2 time periods from a single centre or data for 2 different centres in a single paper and the Neonatal Perinatal

Database of India (NNPD)7 provided data separately for inborn and out-born neonates. No studies for Sri Lanka,

Maldives or Afghanistan were found during the search period. Since the data set belonging to a different time

period or different patient population was considered unique, a total of 114 individual reports (India- 76,

Pakistan- 16, Nepal- 14 and Bangladesh- 8) were analysed from 105 studies. The “N” referred to in this article

refers to total number of reports from which data was extracted unless specified as number of studies.

General: Most studies were from single neonatal units reporting data on neonates with presumed or 4data from

in-born or out-born neonates admitted in the neonatal intensive care unit.

The included studies reported on neonates with clinical signs of sepsis with positive bacterial culture or

microbiological laboratory based reports of neonates with suspected sepsis. All studies described the source of

isolated bacteria, the microbiological techniques and the method of determination of antimicrobial sensitivity or

resistance pattern. Among all included studies, pathogenic bacteria were isolated in 24723 cases of sepsis

(36.9% [95% CI 36.2 - 37.7]). Gram negative bacteria constituted 62% of all isolates.

Antimicrobial Resistance: The overall AMR pattern of important pathogens to various antibiotics in SA region

is given in Table 1. The values are weighted percentages of resistance to individual antibiotic weighted by the

total number of isolates of a pathogen tested. Supplementary Table 2 lists the details studies included along with

the definitions used.

MDR: The lack of homogeneity in definition for multidrug resistant (MDR) bacteria in the studies resulted in

data that were difficult to compare. Recently in 2012, a group of experts came together to provide consensus and

uniformity in defining multidrug resistance (MDR), extreme drug resistance (XDR) and pan-drug resistance

(PDR).8 The group defined MDR as non-susceptibility to at least one agent in three or more antimicrobial

categories. XDR was defined as non-susceptibility to at least one agent in all but two or fewer antimicrobial

categories and PDR was defined as non-susceptibility to all agents in all antimicrobial categories. The most

commonly used MDR definition for gram negative organism is resistance to 3 or more antimicrobial agents. We

used XDR definition as mentioned; for DeNIS study9 we analyzed the XDR rates for pathogens resistant to all

antibiotics except colistin (the data used from Joshi et al10 reported resistant to all antibiotics; however we

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considered it into XDR (instead of PDR) assuming since colistin was not tested, these pathogens may have been

sensitive to it, given colistin was virtually never used in the pre-2000 era and colisitn resistance has been

reported only for last few years).

Limitations: This systematic review has several limitations. It was a limited review of a single database with

data extraction done by a single author (SS), but PubMed is the largest database and extraction was randomly

cross-checked by the first co-author for 10% studies. Conference proceedings and other grey literature were not

searched. Most studies barring a few were hospital based single centre studies managing both inborn and

outborn (home delivered or delivered at other health facilities) neonates with or without underlying medical or

surgical conditions and of varied gestational age and birth weight. We did not contact the authors of included

studies for more information than provided. The review also encompasses data from blood culture based reports

providing little clinical information on study subjects. Finally quality assessment of the included studies was not

performed.

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Confidential: For Review OnlyRecords identified through

database searching

(n =2577 )

Scr

een

ing

Incl

ud

ed

Eli

gib

ilit

y

Iden

tifi

cati

on

Additional records identified

through other sources

(n = 19)

Records after duplicates removed

(n=2517)

Records screened

(n = 2536)

Records excluded

(n = 2337)

Full-text articles assessed

for eligibility

(n = 199)

Full-text articles excluded,

with reasons

(n = 94)

• Outbreaks= 12

• Reviews=32

• Children= 17

• Bacterial isolates not

reported individually =20

• Infections other than

blood stream= 3

• Mixed organisms =1

• Duplicates=2

• Commentary=1

• Relevant data not Studies included in

qualitative synthesis

(n = 105)

Flow diagram for the systematic review (based on PRISMA 2009 flow chart -Preferred Reporting

Items for Systematic Reviews and Meta-Analyses)

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Confidential: For Review Only Supplementary Table 1: Antimicrobial resistance pattern of common pathogens in South Asia

Organism

N= No. of

isolate

Staph.

aureus

N= 2437

Klebsiella

spp

N= 4312

E. coli

N= 2798

Acinetobacter

spp

N= 1347

Pseudomonas

spp

N= 1445

Enterobacter

spp

N= 516

Ampicillin

69

(67.3-

70.6)

N=2266

86.8

(85.8-

87.3)

N=2806

88.2

(87-

89.5)

N=2196

86.2

(83.8-88.5)

N=633

78.5

(76.6-80.5)

N=1059

92.3

(90.2-94.4)

N=497

Gentamicin

54.5 (52.4-

56.6)

N=1773

75.3

(74-76.7)

N=2954

67.9 (66-

69.8)

N=2254

68.1

(65.1-71)

N=792

60.9

(58.6-63.1)

N=1387

76.3

(73-79.6)

N=455

Amikacin

34 (31.9-

36.1)

N=1497

45.6

(44.3-47)

N=4128

31.5 (29.7-

33.2)

N=2387

63.5

(61.2-65.7)

N=1317

36.7

(34.2-39.2)

N=1147

30

(27-34.4)

N=504

Cefotaxime 51.2

(49-53.3)

N=1753

72.5 (71.3-

73.7)

N=4126

66.9 (65.3-

68.6)

N=2745

80.3

(78.2-82.4)

N=1121

58.8

(56.3-61.2)

N=1154

75.5

(72-79)

N=494

Ciprofloxacin

42.4

(40.6-

44.3)

N=2196

53.8

(52.4-

55.2)

N=4054

40.5

(38.8-

42.3)

N=2720

70.3

(68.1-72.5)

N=1332

33.5

(31.4-35.6)

N=1435

38.7

(35.4-42)

N=504

Meropenem

Not Applicable

10.4

(9.4-11.5)

N=2540

8.1

(6.8-9.4)

N=1551

64.8

(62.2-67.4)

N=828

17.6

(15.3-20)

N=560

9.5

(4.9-14.2)

N=127

Ceftazidime 74.5

(73-75.9)

N=2455

69.4

(67.4-

71.4)

N=1773

73.6 (70.8-76.3)

N=718

49.5 (47.1-51.8)

N=1170

66.4 (62.4-70.4)

N=456

Piperacillin-

taobactam

25 (23-26.8)

N=1608

57.4

(53.5-

61.2)

N=400

64.6 (62.1-67.2)

N=935

28 (24.7-31.2)

N=468

-

Polymyxin 6.6

(4.4-9)

N=293

30.6

(14.7-

46.6)

N=28

2.9 (0-5)

N=200

10.1 (6.1-14.1)

N=183

33.5 (4.9-62.1)

N=9

Tigecycline 6

(3-8.6)

N=307

4.3

(2-7)

N=192

16.8

(12.9-20.8)

N=317

67.4

(60-74.9)

N=72

2

(0-5.7)

N=57

Cefipime 51.2

(44-58.3)

N=143

44.3

(36.9-

51.8) N=88

71.1

(64.9-77.3)

N=172

27.7

(24-31.4)

N=180

45.4

(29.6-61.2)

N=11

Cloxacillin

61.2

(58.5-

63.9)

N=873

Not Applicable

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Confidential: For Review OnlyMethicillin

46.5

(41.9-

51.1)

N=310

Linezolid 2.8

(1-4.7)

N=281

Vancomycin

19.1

(17.4-

20.8)

N=1575

Data represents weighted median (95%CI), N= no. of isolates tested, unless stated otherwise; colour code: less

than 50% resistance is shaded green, greater than or equal to 50% is shaded orange.

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Supplementary Table 2: List of studies reporting MDR from South Asia Author,

country

Definition of MDR Proportions of MDR organisms

Viswanathan et

al (2012, India)3

resistance to all 3 groups of antibiotics

studied namely ampicillin, gentamicin

and cefotaxime/ceftazidime

�Klebsiella spp. (58/60, 96%)

�E. coli (18/25, 72%)

�Acinetobacter spp. (13/15, 87%)

Viswanathan et

al (2014),

India11

resistance to any 3 classes: 3rd

generation cephalosporins,

aminoglycosides and fluoroquinolones

�Acinetobacter spp. (15/30, 50%)

O Carbapenem Resistance (9/30, 30%)

O Pan-resistance (5/30, 16.6%)

Roy et al

(2015), India12

resistance to 2 or more classes of drugs �E.coli (52/67, 78% ); most common (24%, 16/67)

resistance pattern: ‘ciprofloxacin-cefotaxime-

amikacin-trimethoprim/

sulfamethoxazole’

DeNIS

collaboration

(2016), India9

any 2 of 5 classes: Extended spectrum

cephalosporins, carbapenem,

aminoglycoside, fluroquinolone and

piperacillin-tazobactam

�Acinetobacter spp (181/222, 82%)

�Klebsiella spp (91/169, 54%)

�Escherichia coli (52/137, 38%)

�Pseudomonas spp. (13/68, 19%)

�Enterobacter spp. (22/44, 50%)

Dhaneria et al

(2018), India13

resistance to at least 3 antibiotics �Klebsiella spp. (9/11, 86%)

�Pseudomonas spp. ( 5/6 ,8 2%)

�E coli (4/5, 80%)

�Proteus spp. (3/4, 75%)

Khanal et al

(2015), Nepal14

resistance to 2 or more drugs �Gram-positive (40/61, 65%)

�Gram-negative (8/8, 100%)

�Overall 48/69, 69.5%)

Joshi et al

(2000), India10

resistance to all antibiotics tested �Klebsiella spp. (7/70, 10%)

� E. coli (2/36, 6.2%)

�Acinetobacter spp.(4/18, 22.2%)

�Pseudomonas spp. (19/88, 22%)

Ansari et al

(2015), Nepal15

most antibiotics �Klebsiella spp (3/9, 33%)

�Enterobacter spp (6/6, 100%)

�E. coli (2/4, 50%)

Acinetobacter spp. (3/4, 75%)

Srivastava et al

(2014), India16

more than 3 groups of antibiotics · Gram negative bacilli (27/108, 25%)

Haque et al

(2014),

Bangladesh17

resistance to 3 or more OR combined

resistance against ceftazidime and

ceftriaxone

�K. pneumoniae (67/79, 85%)

�

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