Persistence and Fate of Antibiotics in Sewage Prof. Dr. Klaus Kümmerer...

Persistence and Fate of Antibiotics in Sewage

Prof. Dr. Klaus Kü[email protected]

Pharmaceutical Sewage During Influenza Pandemic

Somerville College, University of Oxford, 3 March 2009

Department of Environmental Health Sciences

Some DataConsumption of Antibiotics

Medicine Veterinary Growth Promoters

65 %

6 %29 %USA 23 000 t ?

Other countries ?

World ?

EU: total 13 216 t (1999)

* FEDESA 2001

** Estimation based on data of the Union of Concerned Scientists (2001)

(only until 2005 in the EU)

Some Data

• 250 different active compounds authorized in Germany(antibiotics, antimycotics)

• Consumption: Germany 3-6 g per capita and year (regional differences)

•

• Data Europe:

Alexy et al., Acta Hydrochim. Hydrobiol. 34, 587-592, 2006

http://www.esac.ua.ac.be/

0

20

40

60

80

100

120

Penic

illin

s

Cephal

osp.

Sulfo

namid

es

Amin

oglyko

s.

Tetra

cycl

ines

Mac

rolid

es

Glyco

peptid

es

Quinolo

nes

Other

s

t/y

r

Prescriptions by Practitioners

Hospitals

Emissions of Antibiotics Into Municipal SewageUsage 1998: 412 t (Germany)

Emission 1998: 277 t (Germany)Thereof hospitals 92 t (Germany)

Kümmerer und Henninger, Clinical Microbiology and Infection, 9, 1203-1211, 2003

What Happens in the Sewage Treatment Plant?

© Abwasserzweckverband Breisgauer Bucht, http://www.azv-breisgau.de/

Elimination of the compounds?

In the ng-µg/L in the effluent!

• Antibiotics: 0 -100%

• Cytotoxics 0 -100%

• Hormones: 20 - 80%

• Statins (Lipid lowering) 0 - 50%

• Pain killers 0 - 50%

• Anti depressivs 0 - 50%

• Disinfectants 0 -100%

• Diagnostics 0 - 20%

Elimination of Pharmaceuticalsin Municipal STPs

…., Golet et al. 2002, Färber et al. 2002, Kolpin et al. 2002, Sacher et al. 2001, Kümmerer et al. 2000, Hamscher et al. 2002,

Zuccato et al. 2001, Hirsch et al. 1999, Ternes 1998ff, Heberer 1996ff, Richardson und Bowron 1985, ….

Elimination in the environment is the sum of:

• Biotransformation

• Photolysis

• Hydrolysis

• Oxidation/Reduction

• Sorption

Key Processes for Elimination

Key Properties for Elimination

• Water solubility

• Partition coefficients (log Pow, log Koc)

• Redox potential

• Degree of saturation

• Types of functional groups

• Electrical charges

• Acid/base constants (pKas)

Roxithromycin

0

20

40

60

80

100

Zulauf Ablauf Belebt-schlamm

Überschuss-schlamm

Kon

zent

ratio

n [n

g/l]

oder

[µ

g/kg

TS

]

Structure Matters: Impact of Structure on Elimination in a STP

Clarithromycin

0

20

40

60

80

100


Überschuss-schlamm

Ko

nze

ntr

atio

n [

ng

/l] o

der

[µ

g/k

g T

S]

Con

cent

ratio

n(n

g/L;

µg

/kg

d.m

.)

Con

cent

ratio

n(n

g/L;

µg

/kg

d.m

.)

influent influentsludge effluent sludgeeffluent surplus sludge

surplussludge

Alexy, Sacher, Wenz, Kümmerer, Acta hydrochim. Hydrobiol., 2006

Roxithromycin

0

20

40

60

80

100


Überschuss-schlamm

Kon

zent

ratio

n [n

g/l]

oder

[µ

g/kg

TS

]

Structure Matters: Impact of Structure on Elimination in a STP

Clarithromycin

0

20

40

60

80

100


Überschuss-schlamm

Ko

nze

ntr

atio

n [

ng

/l] o

der

[µ

g/k

g T

S]

Con

cent

ratio

n(n

g/L;

µg

/kg

d.m

.)

Con

cent

ratio

n(n

g/L;

µg

/kg

d.m

.)

influent influentsludge effluent sludgeeffluent surplus sludge

surplussludge

NOCH2OC2H5OCH3

Alexy, Sacher, Wenz, Kümmerer, Acta hydrochim. Hydrobiol., 2006

Compound specific approach needed !

Which Compound?

Pharmaceuticals Are Different!Ciprofloxacin

OH

N

OH

O

N

HN

O

F

Ciprofloxacin

Acidic groups

Basic groups

Optimised for biological activity and stability.Several different functional groups within on and the same molecule.

Ciprofloxacin: Micro-species as a function of pH

Zwitterion:Isoelectric point at pH 7

(Primary) Elimination vs. (Total) Mineralization

What degree is needed?

Physical Chemical Instability of Antibiotics

0,00

0,03

0,06

0,09

0,12

0,15

0,18

k [

1/d

]

4°C Dunkelheit 15°C Dunkelheit 20°C Dunkelheit 20°C Lichtdarknessdarkness darkness light

Kümmerer and co-workers, unpublished

Stability Profile of Ceftriaxone(Fitted According to Arrhenius-Equation)

0

1

2

3

4681012141618205 10 15 20 25

Ko

nze

ntr

ati

on

[m

g/l

]

0 [mg/l]1 [mg/l]2 [mg/l]3 [mg/l]C

on

cen

tra

tio

n

DAY Temperature

Kümmerer and co-workers, unpublished

Degradation of Structurally Closely Related Penicillins

Piperacillin Amoxicillin

N

S

OOH

H

HN

O

O

Benzylpenicillin

SNH

O

H2N

OH

O

N

HOO

N

S

OOH

H

HN

O

O

HNN

O

N

O

O

0

20

40

60

80

100

0 5 10 15 20 25 30day

Elim

inat

ion

in %

HPLC-UVVis: biol. non biol.

DOC: biol. non biol.

Piperacillin

Day

Elimination and BiodegradationZahn Wellens Test (OECD 302 B)

Kümmerer et al., Chemosphere, in press

m/z 518 (+mode)Piperacillin

m/z 536 (+ mode)hydrolysedPiperacillin

N

S

O

O H

H

H N

O

O

HNN

O

N

O

O

NH

S

O

O H

H

H N

O

HNN

O

N

O

O

O HO

(n. biotic) hydrolysis

Degradation of Pieracillin (LC-MS/MS ion trap, -UV-Vis, DOC)

+H2O


0

20

40

60

80

100

0 5 10 15 20 25 30day

Elim

inat

ion

[%

]

0

20

40

60

80

100

0 5 10 15 20 25 30day

Elim

inat

ion

in %

HPLC-UVVis: biol. non biol.

DOC: biol. non biol.

Piperacillin Amoxicillin

Day

Elimination and BiodegradationZahn Wellens Test (OECD 302 B)


SNH

O

H2N

OH

O

N

HO

O

SNH

O

H2N

O

HN

HO

OOH

OHS

NH

O

H2N

OH

O

HN

HO

OOH

+ H2O -C6H5

m/z 366 (+ mode) m/z 307 (+ mode)m/z 388 (+ mode)

Amoxicillin hydrolysiertes Amoxicillin hydrolysiertes Amoxicillinohne Benzenring

non biotic biotic

???

?

Amoxicillin hydrolysed Amoxicillin hydrolysed Amoxicillinwithout phenol ring

Bio-degradation

Bio-mineralization

(n. biotic) Hydrolysis

-C6H6O

Degradation of Amoxicillin (LC-MS/MS ion trap, -UV-Vis, DOC)


t1/2 Benzylpenicillin ≈ 2 * t1/2 Amoxicillin

Photo-degradation of Ciprofloxacin

Vasconcelos T. G., Henriques D.M., König, A., Martins A.F., Kümmerer K., Chemosphere, accepted

0 2 4 6 8 10 12 Time [min]0

20

40

60

80

100

Intens.mAU

0 2 4 6 8 10 12 Time [min]0

20

40

60

80

100

Intens.mAU

0 2 4 6 8 10 12 Time [min]0

20

40

60

80

100

Intens.mAU

Ciprofloxacin

Photo-transformation products 4 min Photo-transformation products 2 min


N

F

N

O O

OH

HN

NN

O O

OH

HN CH3

O

N

F

NH

O O

OH

NH2

NNH

O O

OH

NH2

N

HO

N

O O

OH

HN

Product 1

Product 4

Product 3

Product 2

CIPRO

N

F

N

O

HN

Product 5

Photo-degradation of Ciprofloxacin

0

0,5

1

1,5

2

2,5

3

3,5

4

4,5

5

0 1 7 14 28days

Cip

ro C

on

ce

ntr

ati

on 0 min

2 min4 min


0 min: Ciprofloxacin

Biodegradability of Photo Products of Ciprofloxacin

• Advanced filtration technologies (reversed osmosis, membrane filtration, nanofiltration), and (photo)oxidation technologies are emerging.

• Efficiency may depend strongly on the type of compound. Reaction products?

• Resistance and bio-membrane (enrichment, residence time)

• Costs?

• Storm water?

• Infiltration of the ground before STP?

• Not compatible with green chemistry.

Advanced Effluent Treatment (1)

• Working for new compounds?

• Not possible in less developed countries

Advanced Effluent Treatment (2)

Summary - Questions

• Which compound (pH, metabolites, transformation products)?

• Which bacterial consortium?• Significance of resistance?• Temperature?• Concentration?• Primary degradation vs. mineralization?• Transformation products still active?• Properties?

Properties of Mixtures of Pharmaceuticals:

Expectation and Reality

EC50

5-Fluorouracil (5-FU): 260 µg/l

Amoxicillin: 2,000 µg/l

5-FU + Amoxicillin: 6 µg/l

Cefazolin: 120,800 µg/l

5-FU + Cefazolin: 8 µg/l

Mixture: 5-FU – ß-Lactams Growth Inhibition Test with Bacteria (EN ISO 10712 :

1995)

Factor: 4*102 (5-FU) – 1,5 *104 (Cefazolin)

Alexy and Kümmerer, in preparation

Looking forward to the discussion ?

Discussion

Looking forward to the discussion !

Persistence and Fate of Antibiotics in Sewage Prof. Dr. Klaus Kümmerer...

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