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SEWPROF ITN A new paradigm in drug use and human health risk assessment: Sewage profiling at the community level

Erika Castrignanò University of Bath, United Kingdom

Supervisor: Dr. Barbara Kasprzyk-Hordern

Meeting: WG 2 Meeting

Date and time: 27-28th October 2014

Location: Hal Luqa, Luqa, Malta

COST is supported by the

EU Framework Programme

Horizon 2020

ESF provides the COST

Office through an EC

contract


OUTLINE

• Antibiotics use and antimicrobial resistance

• Wastewater-based approach

• Methodologies

• Epidemiological studies

• Conclusions


ANTIBIOTIC USE IN EUROPE

ECDC-Annual epidemiological report -Reporting on 2010 surveillance

data and 2011 epidemic intelligence data 2012

2008

2009

2010

Trends in the consumption of antibacterials for systemic use (ATC group

J01) in the community (outside of hospitals), EU/EEA Countries, 2008-10

Consumption of antibacterials for systemic use (ATC group

J01) in the hospitals sector, EU/EEA Countries, 2010

Penicillins

Cephelosporins and other

beta lactams

Tetracyclines

Macrolides, lincosamides and

streptogramins

Quinolones

Sulfonamides and thrimetoprim

Other J01 classes

EE

LV

NL

LT

SE

SI

DE

AT

HU

NO

DK

CZ

BG

FI

UK

ES

IE

PL

MT

PT

IS

SK

IT

FR

BE

LU

CY

EL

RO

EE

LV

NL

LT

SE

SI

DE

AT

HU

NO

DK

CZ

BG

FI

UK

ES

IE

PL

MT

PT

IS

SK

IT

FR

BE

LU

CY

EL


ANTIMICROBIAL RESISTANCE

AMR


ANTIMICROBIAL RESISTANCE


ANTIMICROBIAL RESISTANCE SURVEILLANCE IN EUROPE 2012

Results presented in surveillance report from ECDC are based:

• on antimicrobial resistance data from invasive isolates reported to EARS-Net by

30 EU/EEA countries in 2013 (data referring to 2012),

• on trend analyses of EARSS/EARS-Net data reported by the participating

countries during the period 2009 to 2012



Escherichia coli

Third-generation cephalosporins

Fluoroquinolones Aminoglycosides

Combined resistance



Klebsiella pneumoniae

Third-generation cephalosporins

Fluoroquinolones Aminoglycosides

Combined resistance Carbapenems



• Carbapenem resistance and resistance to multiple antimicrobial groups

were also common in Pseudomonas aeruginosa and Acinetobacter spp.

isolates.

• Resistance trends in gram-positive bacteria showed a more diverse

pattern across Europe.

• The trends for Streptococcus pneumoniae and enterococci are generally

stable, but with large inter-country variations in the percentage of

resistant isolates.

• Meticillin-resistant Staphylococcus aureus (MRSA) remains a public

health priority as the percentage is still above 25% in seven of the 30

reporting countries, with a population-weighted EU/EEA mean of 17.8%.



• For several antimicrobial agent–microorganism combinations, an

overall north-to-south and west-to-east gradient is evident in Europe.

• Differences in infection control practices

and antimicrobial use in the reporting

countries.

• Differences in effective prevention and

control efforts aimed at reducing the

selection and transmission of resistant

bacteria.

• The continuous loss of effective

antimicrobial therapy against gram

negative microorganisms.

• The need for comprehensive strategies

targeting all health sectors.

Countries contributing AMR data for 2012

to EARS-Net

Non participating Countries

Participating Countries


A real-time profiling of community-wide health and lifestyle is a

needed approach for the investigation of determinants of health-

related states.

World Health Organization (WHO)

Analysis of human

biomarkers statistics on health

themes

analytical studies

surveillance and descriptive studies (alert organism tracking, enhanced routine

surveillance, targeted surveys)


WASTEWATER ANALYSIS

How can we analyse a real-time profiling of a community?

CONSUMPTION

EXCRETION

MET

AB

OLI

SM

Multiplying with the flow rate of the wastewater stream (L/day)

Multiplying with CF (excretion pattern)

Dividing with amount of inhabitants present in the catchment area of the WWTP


WASTEWATER-BASED EPIDEMIOLOGY

Overview of the sewage

epidemiology approach

(modified from van Nuijs, A.L., et al.,

Sewage epidemiology-a real-time

approach to estimate the

consumption of illicit drugs in

Brussels, Belgium. Environ Int, 2011.

37(3): p. 612-21.)

Measured concentration of compounds

Multiplying with CF (degradation during transport of ww to WWTP)

Corrected concentration

Massloads of compounds (mg/day)

Amount of use illicit drug (mg/day)

Amount of use illicit drug (mg/day per 1000 inhabitants)


METHODOLOGIES

UHPLC-MS/MS (QqQ or QTOF)

has been used for target analysis

of chiral compounds

Sample

preparation:

filtration

Sample

preparation:

SPE

MS data interpretation

Sampling

Antibacterial drugs

WWTP influent Cilfynydd

WWTP effluent Cilfynydd

Trimethoprim 1879 ng/L 1004 ng/L

Sulfamethoxazole <LOQ 12 ng/L

Amoxicillin <LOQ <LOQ

Chloramphenicol <LOQ <LOQ

Erythromycin 404 ng/L 830 ng/L

Metronidazole 2608 ng/L 373 ng/L


METHODOLOGIES

B. Kasprzyk-Hordern et al. Anal Bioanal Chem (2008) 391:1293–1308



• Seasonal change in plant

A is caused by the

increased appearance of

epidemics during the

winter

L. Birošová et al. / Science of the Total Environment 490 (2014) 440–444

• In plant B, the same or

higher concentrations of

some antibiotics were

detected also in August.

hospitals and health

care facilities

• Misuse antibiotics Plant A (in 2010, 6th place in EU and

usage of antibiotics for prevention)



Temporal range: pandemic,

late- and inter-pandemic

Singer AC, Ja¨rhult JD, Grabic R, Khan GA, Lindberg RH, et al. (2014) Intra- and Inter-Pandemic

Variations of Antiviral, Antibiotics and Decongestants in Wastewater Treatment Plants and

Receiving Rivers. PLoS ONE 9(9): e108621.

Understand the differential

pharmaceutical use patterns

during the pandemic

Examine the suitability of

employing a wastewater

epidemiology approach for

the estimation of drug users



WW epidemiology approach will need to address:

1. Heterogeneity in the temporal distribution of prescriptions over time

2. Heterogeneity in the spatial distribution of prescriptions (across the UK) over time

3. Heterogeneity in in vivo and environmental stability of the antibiotic, including sewage

pipes prior to reaching the WWTP inlet

4. Variability in compliance rate, sample size and sampling method

5. Variability in environmental temperatures and precipitation

Singer AC, Ja¨rhult JD, Grabic R, Khan GA, Lindberg RH, et al. (2014) Intra- and Inter-

Pandemic Variations of Antiviral, Antibiotics and Decongestants in Wastewater Treatment

Plants and Receiving Rivers. PLoS ONE 9(9): e108621.



Y. Xiao et al. / J. Chromatogr. A 1214 (2008) 100–108

• Different consumption

style in China



• ~ 107–1010 CFU per day per inhabitant equivalent can be discharged by the final

effluent of UWTP and could have any kind of acquired antibiotic resistance.

• Only 1% of the total of the culturable fraction of the bacterial population is being

considered.

L. Rizzo et al. / Science of the Total Environment 447 (2013) 345–360

• 140 clinically relevant genes, encoding resistance to the

different classes of antibiotics, were detected

(Szczepanowski et al., 2009).

• Occurrence of antimicrobial residues, selecting

resistance phenotypes, may also disturb the indigenous

bacterial communities (Novo et al., in press).

• Current knowledge about the relationship between

antibiotics and the spread of ARG in microbial

communities: the result of retrospective evidences.



L. Rizzo et

al. /

Science of

the Total

Environme

nt 447

(2013)

345–360

In an attempt to establish a relationship between the most severe cases reported in

clinical settings and environment, the search for the last generation antibiotic

resistant determinants is also reported in UWTP studies (Araújo et al., 2010;

Czekalski et al., 2012; Figueira et al., 2011a,b; Gajan et al., 2008; Parsley et al.,

2010; Szczepanowski et al., 2009).



L. Rizzo et

al.

Science of

the Total

Environm

ent 447

(2013)

345–360

Ciprofloxacin resistant E. coli : significantly higher prevalence in the final

effluent than in the raw inflow of an UWTP. Ferreira da Silva et al., 2007

Acinetobacters: resistance to amoxicillin/clavulanic acid, chloramphenicol,

rifampin, and multi-drug significantly increased from the raw influent samples to

the final effluent samples, and was significantly higher in the downstream samples

than in the upstream samples. Y. Zhang et al. (2009)

Carbapenem resistance: Not been reported in recent studies concerning

wastewaters (Figueira et al., 2011a; Łuczkiewicz et al., 2010).

… it will be a matter of time

L.

Birošová

et al.

Science of

the Total

Environme

nt 490

(2014)

440–444

Most coliforms are resistant to

ampicillin:

it is in accordance with the

frequent prescription of β-lactams

in Slovakia


Prof. Ed Feil Professor of Microbial Evolution

University of Bath

United Kingdom

Supervisors:

• Exploring antibiotics profiling and microbial resistance at community level via

wastewater-based epidemiology

• Understanding the origin of a drug residue, recognizing the direct consumption

from its disposal

• Monitoring of changing patterns of antibacterial drugs use

Dr. Barbara Kasprzyk-Hordern Dept. Chemistry, University of Bath

United Kingdom

Dr. Sara Castiglioni Istituto di Ricerche Farmacologiche Mario

Negri

Italy

Dr. Anneke Lubben Mass Spectrometrist ,University of Bath

United Kingdom


CONCLUSIONS

Wastewater-based epidemiology:

Evidence-based and real time estimates of a

community antibacterial usage

• Spatial and temporal differences among Countries

• Changes in consumption trends

• Monitoring of AMR


EU-International Training Network SEWPROF, Marie

Curie Actions (Project No.317205)

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