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Monitoring anti-infectives and antibiotic resistance genes: with focus on analytical method development, effects of antibiotics and national perspectives
Umeå University, Faculty of Science and Technology, Department of Chemistry.
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Antibiotics are biologically active and are globally used in humans and animal medicine for treatment and in sub-therapeutic amounts as growth promoters in animal husbandry, aquaculture and agriculture. After excretion, inappropriate disposal and discharge from drug production facilities they enter into water bodies either as intact drugs, metabolites or transformed products. In water environments they promote development of antibiotic resistance genes (ARGs) which could serve as a reservoir and be horizontally transferred to human-associated bacteria and thus contribute to AR proliferation. Measurement of antibiotics has been revolutionized with the usage of solid phase extraction (SPE) for enrichment followed by Liquid chromatography mass spectrometry (LC-MS). On-line SPE coupled to LC-MS/MS has the advantages of high sample throughput, low sample preparation time and minimal solvent utilization.  Constructed wetlands (CWs) are potential alternatives to conventional treatment plants to remove organic pollutants. A study at Plönninge, Halmstad was performed to assess the impact of bacterial community pattern and development of resistance in spiked (n=4) and control (n=4). CWs were spiked with antibiotics at environmentally relevant concentrations continuously for 25 days. Shannon Index (H’) were used to determine the bacterial diversity and real-time PCR detected and quantified antibiotic resistance genes (ARGs) sulI, tetA, tetB, erm, dfrA1, qnrS and vanB and class 1 integrons intI1. No significant differences in bacterial compositions or in ARGs or integron concentrations could be discerned between exposed and control wetlands. A study conducted in Northern Pakistan showed that the antibiotic levels in most studied rivers were comparable to surface water measurements in unpolluted sites in Europe and the US. However, high levels of antibiotics were detected in the river in close vicinity of the 10 million city Lahore, e.g. 4600 ng L−1 sulfamethoxazole. Highest detected levels were at one of the drug formulation facilities, with measured levels up to 49000 ng L−1 of sulfamethoxazole for example. The highest levels of ARGs detected, sul1 and dfrA1, were directly associated with the antibiotics detected at the highest concentrations, sulfamethoxazole and trimethoprim. In the study in UK, sewage epidemiology surveillance is used to measure the oseltamivir carboxylate (OC), metabolite of oseltamivir (parent drug) in twenty four time proportional hourly influent samples from two WWTPs and then back-calculations were made to assess the compliance of drug.  Predicted users of oseltamivir, based on measured OC in waste water, ranged from 3-4 and 120-154 people for the two WWTP catchments, respectively, which are consistent with the projected use from national antiviral allocation statistics, 3-8 and 108-270, respectively. Scenario analysis suggests compliance was likely between 45-60% in the study regions. 

Place, publisher, year, edition, pages
Umeå: Umeå University , 2012. , 48 p.
Keyword [en]
method development, on-line solid phase extraction liquid chromatography mass spectrometry (SPE LC-MS/MS), antibiotics, anti-infectives, constructed wetlands (CWs), denatured gradient gel electrophoresis (DGGE), percentage removal efficiency (PRE), shannon index, antibiotic resistance genes (ARGs), real-time polymerase chain reaction (RT-PCR), drug formulation facilities (DFF), wastewater, epidemiology, pandemic, influenza, compliance
National Category
Analytical Chemistry Microbiology
Identifiers
URN: urn:nbn:se:umu:diva-61682ISBN: 978-91-7459-531-4 (print)OAI: oai:DiVA.org:umu-61682DiVA: diva2:571404
Public defence
2012-12-13, N430, Naturvetarhuset, Umeå universitet, Umeå, 10:00 (English)
Opponent
Supervisors
Available from: 2012-11-22 Created: 2012-11-22 Last updated: 2012-11-22Bibliographically approved
List of papers
1. The development and application of a system for simultaneously determining anti-infectives and nasal decongestants using on-line solid-phase extraction and liquid chromatography-tandem mass spectrometry
Open this publication in new window or tab >>The development and application of a system for simultaneously determining anti-infectives and nasal decongestants using on-line solid-phase extraction and liquid chromatography-tandem mass spectrometry
2012 (English)In: Journal of Pharmaceutical and Biomedical Analysis, ISSN 0731-7085, E-ISSN 1873-264X, Vol. 66, 24-32 p.Article in journal (Refereed) Published
Abstract [en]

A method for the simultaneous analysis of antibiotics, antiviral and nasal decongestants in treated sewage effluent and surface water has been developed and validated. The method uses on-line solid phase extraction (SPE) of injected high-volume samples in conjunction with liquid chromatography-tandem mass spectrometry (LC-MS/MS). This method includes a range of antibiotics (Trimethoprim, Oxytetracycline, Ofloxacin, Norfloxacin, Ciprofloxacin, Azithromycin, Doxycycline, Sulfamethoxazole, Erythromycin and Clarithromycin), an antiviral (Oseltamivir) and nasal decongestants (Naphazoline, Oxymetazoline and Xylometazoline). The method's detection limits (MDLs) ranged from (0.2ngL(-1)) to (3.1ngL(-1)), based on a 1mL extraction volume. Its intra-day precision was determined by performing nine runs with 200ngL(-1) samples; the intra-day relative standard deviation (RSD) ranged from 1% to 19%. Inter-day precision was determined by analyzing samples in triplicate over the course of three days, yielding relative standard deviations ranging from <5% to <26%. The linearity (R(2)) for all compounds tested was >0.90. Spike relative recoveries ranged from 40% to 157% and 40% to 152% for STP effluent and surface water samples, respectively. Finally, the method was used to analyze real effluent and surface water.

Keyword
Method development/validation; On-line solid-phase extraction; LC–MS/MS antibiotics; Anti-infectives; Nasal decongestants
National Category
Chemical Sciences
Identifiers
urn:nbn:se:umu:diva-55100 (URN)10.1016/j.jpba.2012.02.011 (DOI)000304843600003 ()22459504 (PubMedID)
Available from: 2012-05-08 Created: 2012-05-08 Last updated: 2017-12-07Bibliographically approved
2. At environmentally-relevant concentrations, antibiotics do not affect bacterial community patterns in constructed wetlands
Open this publication in new window or tab >>At environmentally-relevant concentrations, antibiotics do not affect bacterial community patterns in constructed wetlands
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(English)Article in journal (Other academic) Submitted
National Category
Chemical Sciences
Identifiers
urn:nbn:se:umu:diva-61677 (URN)
Available from: 2012-11-22 Created: 2012-11-22 Last updated: 2012-11-22Bibliographically approved
3. Exposure of constructed wetlands to environmental concentrations of antibiotics show no effect on antibiotic resistance gene selection and expression
Open this publication in new window or tab >>Exposure of constructed wetlands to environmental concentrations of antibiotics show no effect on antibiotic resistance gene selection and expression
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(English)Manuscript (preprint) (Other academic)
National Category
Chemical Sciences
Identifiers
urn:nbn:se:umu:diva-61678 (URN)
Available from: 2012-11-22 Created: 2012-11-22 Last updated: 2012-11-22Bibliographically approved
4. Occurrence and abundance of antibiotics and resistance genes in rivers, canal and near drug formulation facilities: a study in Pakistan
Open this publication in new window or tab >>Occurrence and abundance of antibiotics and resistance genes in rivers, canal and near drug formulation facilities: a study in Pakistan
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2013 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 6, e62712- p.Article in journal (Refereed) Published
Abstract [en]

Antibiotic resistance (AR) is a global phenomenon that has severe epidemiological ramifications world-wide. It has been suggested that antibiotics that have been discharged into the natural aquatic environments after usage or manufacture can promote the occurrence of antibiotic resistance genes (ARG). These environmental ARGs could serve as a reservoir and be horizontally transferred to human-associated bacteria and thus contribute to AR proliferation. The aim of this study was to investigate the anthropogenic load of antibiotics in Northern Pakistan and study the occurrence of ARGs in selected samples from this region. 19 sampling sites were selected; including six rivers, one dam, one canal, one sewage drain and four drug formulation facilities. Our results show that five of the rivers have antibiotic levels comparable to surface water measurements in unpolluted sites in Europe and the US. However, high levels of antibiotics could be detected in the downstream river in close vicinity of the 10 million city Lahore, 1100, 1700 and 2700 ng L-1 for oxytetracycline, trimethoprim, and sulfamethoxazole respectively. Highest detected levels were at one of the drug formulation facilities, with the measured levels of 1100, 4100, 6200, 7300, 8000, 27000, 28000 and 49000 ng L 21 of erythromycin, lincomycin, ciprofloxacin, ofloxacin, levofloxacin, oxytetracycline, trimethoprim and sulfamethoxazole respectively. ARGs were also detected at the sites and the highest levels of ARGs detected, sulI and dfrA1, were directly associated with the antibiotics detected at the highest concentrations, sulfamethoxazole and trimethoprim. Highest levels of both antibiotics and ARGs were seen at a drug formulation facility, within an industrial estate with a low number of local residents and no hospitals in the vicinity, which indicates that the levels of ARGs at this site were associated with the environmental levels of antibiotics

National Category
Chemical Sciences
Identifiers
urn:nbn:se:umu:diva-61679 (URN)10.1371/journal.pone.0062712 (DOI)000321148400001 ()
Available from: 2012-11-22 Created: 2012-11-22 Last updated: 2017-12-07Bibliographically approved
5. Compliance to Oseltamivir among two populations in Oxfordshire, United Kingdom affected by Influenza A(H1N1)pdm09
Open this publication in new window or tab >>Compliance to Oseltamivir among two populations in Oxfordshire, United Kingdom affected by Influenza A(H1N1)pdm09
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(English)Article in journal (Other academic) Submitted
National Category
Chemical Sciences
Identifiers
urn:nbn:se:umu:diva-61681 (URN)
Available from: 2012-11-22 Created: 2012-11-22 Last updated: 2016-05-16Bibliographically approved

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