DOI: https://doi.org/10.18370/2309-4117.2020.51.25-31

Modern approaches to the choice of antimicrobial agents for pelvic inflammatory diseases: the role of innovative microbiological methods

О. А. Бурка, Т. М. Тутченко, Н. Ю. Педаченко, О. М. Кудлай

Abstract


Pelvic inflammatory diseases (PID) is comprehensive term that includes infectious-inflammatory lesions of the endometrium, fallopian tubes and ovaries. PID is one of the main causes of treatment of reproductive aged women by gynecologists, and the cause of impaired reproductive function, chronic pelvic pain syndrome and ectopic pregnancy in the absence of treatment.

This article provides an overview of current clinical guidelines for diagnosis and general treatment approaches of PID. A detailed analysis of modern scientific researches dedicated to the change of the PID’s pathogens structure and the peculiarities of their clinical presentation today. This analysis showed that despite the leading role of sexually transmitted infections, opportunistic flora is of great importance in the pathogenesis of this pathology. Features of the PID’s clinical course include an increase in the recurrence frequency. These features are associated with the growing worldwide phenomenon of antibiotic resistance.

Data from the European Antimicrobial Resistance Surveillance Network report at the European Center for Disease Control “Antibiotic Resistance Surveillance 2017” on the resistance prevalence of clinically relevant pathogenic bacteria to the most commonly used antimicrobials. Nonspecific bacterial pathogens of PID in the European region show a fairly high rate of antibiotic resistance. At the same time, the experience of many countries demonstrates the effectiveness of the strategy of antimicrobial stewardship strategy, one of the main principles of which is microbiological research whenever possible when prescribing antibacterial therapy. Thus regardless of whether representative of the opportunistic flora is a direct cause of a severe PID course or secondary due to previous sexually transmitted diseases, its identification and antibiotic susceptibility testing is critical for the effective treatment of PID (especially severe forms) given the prevalence of antibiotic resistance.

Keywords


sexually transmitted diseases; pelvic inflammatory diseases; opportunistic flora; antibiotic resistance; antibiotic therapy control strategy

References


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Ross, J., Guaschino, S., Cusini, M., Jensen, J. «2017 European guideline for the management of pelvic inflammatory disease.» Int J STD AIDS 29 (2018): 108–14. DOI: 10.1177/0956462417744099

Greydanus, D.E., Bacopoulou, F. «Acute pelvic inflammatory disease.» Pediatr Med 2 (2019): 36. DOI: 10.21037/pm.2019.07.05

Curry, A., Williams, T., Penny, M.L. «Pelvic Inflammatory Disease: Diagnosis, Management, and Prevention.» Am Fam Physician 100 (2019): 357–64.

Das, B.B., Ronda, J., Trent, M. «Pelvic inflammatory disease: Improving awareness, prevention, and treatment.» Infect Drug Resist 9 (2016): 191–7. DOI: 10.2147/IDR.S91260

Moreno, I., Franasiak, J.M. «Endometrial microbiota – new player in town.» Fertil Steril 108 (2017): 32–9. DOI: 10.1016/J.FERTNSTERT.2017.05.034

Khan, K.N., Fujishita, A., Hiraki, K., et al. «Bacterial contamination hypothesis: a new concept in endometriosis.» Reprod Med Biol 17 (2018): 125–33. DOI: 10.1002/rmb2.12083

Tai, F.-W., Chang, C., Chiang, J.-H., et al. «Association of Pelvic Inflammatory Disease with Risk of Endometriosis: A Nationwide Cohort Study Involving 141,460 Individuals.» J Clin Med 7 (2018): 379. DOI: 10.3390/jcm7110379

Stewart, L.M., Stewart, C.J.R., Spilsbury, K., et al. «Association between pelvic inflammatory disease, infertility, ectopic pregnancy and the development of ovarian serous borderline tumor, mucinous borderline tumor and low-grade serous carcinoma.» Gynecol Oncol (2020). DOI:10.1016/j. ygyno.2020.01.027

Zhou, Z., Zeng, F., Yuan, J., et al. «Pelvic inflammatory disease and the risk of ovarian cancer: a meta-analysis.» Cancer Causes Control 28 (2017): 415–28. DOI: 10.1007/s10552-017-0873-3

Frain, A., Fielder, J. «Pelvic inflammatory disease: a review.» O&G Magazine 21.4 (2019). Available from: [https://www.ogmagazine.org.au/21/4-21/pelvic-inflammatory-disease-a-review/], last accessed Feb 22, 2020.

Haque, M. «Antibiotic use, antibiotic resistance, and anti stewardship – a global public consequences.» Bangladesh J Med Sci 18 (2019): 169–70. DOI: 10.3329/bjms.v18i2.40680

Chernick, L.S. «Tubo-Ovarian Abscesses in Nonsexually Active Adolescents: A Rare but Consequential Miss.» J Adolesc Heal 65 (2019): 175–6. DOI: 10.1016/j.jadohealth.2019.04.006

Getahun, A.S., Limaono, J., Ligaitukana, R., et al. «Ovarian abscess caused by Salmonella enterica serovar Typhi: A case report.» J Med Case Rep 13 (2019). DOI: 10.1186/s13256-019-2229-y

Tyan, P., Abi-Khalil, E., Dwarki, K., Moawad, G. «First Described Case of Group B Streptococcus Pelvic Abscess in a Patient with No Medical Comorbidities.» Case Rep Obstet Gynecol 2016 (2016): 1–4. DOI: 10.1155/2016/3724706

Lusby, H., Brooks, A., Hamayoun, E., Finley, A. «Uncommon cause of pelvic inflammatory disease leading to toxic shock syndrome.» BMJ Case Rep 2018 (2018). DOI: 10.1136/bcr-2018-224955

Felz, M.W., Apostol, C.J. «Fatal pneumococcal sepsis from a tuboovarian abscess.» J Am Board Fam Pract 17 (2004): 68–70. DOI: 10.3122/jabfm.17.1.68

Algren, S.D., Strickland, J.L. «Beta hemolytic Streptococcus group F causing pelvic inflammatory disease in a 14-year-old girl.» J Pediatr Adolesc Gynecol 18 (2005): 117–9. DOI: 10.1016/j.jpag.2005.01.007

Yamamoto, T., Kenzaka, T., Mizuki, S., et al. «An extremely rare case of tubo-ovarian abscesses involving corynebacterium striatum as causative agent.» BMC Infect Dis 16 (2016): 1–6. DOI: 10.1186/s12879-016-1860-0

Taylor, G.M., Erlich, A.H., Wallace, L.C., et al. «A tubo-ovarian abscess mimicking an appendiceal abscess: a rare presentation of Streptococcus agalactiae.» Oxford Med Case Reports 2019 (2019). DOI: 10.1093/omcr/omz071

To, V., Gurberg, J., Krishnamurthy, S. «Tubo-Ovarian Abscess Caused by Candida Albicans in an Obese Patient.» J Obstet Gynaecol Canada 37 (2015): 426–9. DOI: 10.1016/S1701-2163(15)30257-7

Okmen, F., Ekici, H., Ari, S.A. «Case Report of a Tubo-ovarian Abscess Caused by Candida kefyr.» J Obstet Gynaecol Canada 40 (2018): 1466–7. DOI: 10.1016/j. jogc.2018.04.025

Trent, M., Bass, D., Ness, R.B., Haggerty, C. «Recurrent PID, subsequent STI, and reproductive health outcomes: Findings from the PID evaluation and clinical health (PEACH) study.» Sex Transm Dis 38 (2011): 879–81. DOI: 10.1097/OLQ.0b013e31821f918c

Safrai, M., Rottenstreich, A., Shushan, A., et al. «Risk factors for recurrent Pelvic Inflammatory Disease.» Eur J Obstet Gynecol Reprod Biol 244 (2020): 40–4. DOI: 10.1016/j. ejogrb.2019.11.004

Sharma, H., Tal, R., Clark, N.A., Segars, J.H. «Microbiota and pelvic inflammatory disease.» Semin Reprod Med 32 (2014): 43–9. DOI: 10.1055/s-0033-1361822

Taylor, B.D., Darville, T., Haggerty, C.L. «Does bacterial vaginosis cause pelvic inflammatory disease?» Sex Transm Dis 40 (2013): 117–22. DOI: 10.1097/OLQ.0b013e31827c5a5b

Centers for Disease Control and Prevention. Pelvic Inflammatory Disease (PID) – 2015 STD Treatment Guidelines. Available from: [https://www.cdc.gov/std/tg2015/pid.htm], last accessed Feb 11, 2020.

Haggerty, C.L. Totten, P.A., Tang, G., et al. «Identification of novel microbes associated with pelvic inflammatory disease and infertility.» Sex Transm Infect 92 (2016): 441–6. DOI: 10.1136/sextrans-2015-052285

Price, M.J., Ades, A.E., Welton, N.J., et al. «Pelvic inflammatory disease and salpingitis: Incidence of primary and repeat episodes in England.» Epidemiol Infect 145 (2017): 208–15. DOI: 10.1017/S0950268816002065

Workowski, K.A., Bolan, G.A. «Centers for Disease Control and Prevention, Sexually transmitted diseases treatment guidelines, 2015.» MMWR Recomm Reports Morb Mortal Wkly Report Recomm Reports 64 (2015): 1–137.

Soper, D.E. Brockwell, N.J., Dalton, H.P., Johnson, D. «Observations concerning the microbial etiology of acute salpingitis.» Am J Obstet Gynecol 170 (1994): 1008–17. DOI: 10.1016/S0002-9378(94)70094-X

Gradison, M. «Pelvic Inflammatory Disease.» Am Fam Physician 85.8 (2012): 791–6.

Price, M.J., Ades, A.E., De Angelis, D., et al. «Risk of pelvic inflammatory disease following chlamydia trachomatis infection: Analysis of prospective studies with a multistate model.» Am J Epidemiol 178 (2013): 484–92. DOI: 10.1093/aje/kws583

Hoenderboom, B.M., Van Benthem, B.H.B., Van Bergen, J.E.A.M., et al. «Relation between Chlamydia trachomatis infection and pelvic inflammatory disease, ectopic pregnancy and tubal factor infertility in a Dutch cohort of women previously tested for chlamydia in a chlamydia screening trial.» Sex Transm Infect 95 (2019): 300–6. DOI: 10.1136/sextrans-2018-053778

Burnett, A.M., Anderson, C.P., Zwank, M.D. «Laboratory-confirmed gonorrhea and/or chlamydia rates in clinically diagnosed pelvic inflammatory disease and cervicitis.» Am J Emerg Med 30 (2012): 1114–7. DOI: 10.1016/J.AJEM.2011.07.014

Jossens, R.M.O., Schachter, J., Sweet, R.L. «Risk Factors Associated With Pelvic Inflammatory Disease of Differing Microbial Etiologies.» Obstet Gynecol 83 (1994): 989–97. DOI: 10.1097/00006250-199406000-00019

Ness, R.B., Soper, D.E., Holley, R.L., et al. «Effectiveness of inpatient and outpatient treatment strategies for women with pelvic inflammatory disease: Results from the Pelvic Inflammatory Disease Evaluation and Clinical Health (PEACH) Randomized Trial.» Am J Obstet Gynecol 186 (2002): 929–37. DOI: 10.1067/mob.2002.121625

Goller, J.L., De Livera, A.M., Fairley, C.K., et al. «Characteristics of pelvic inflammatory disease where no sexually transmitted infection is identified: A cross-sectional analysis of routinely collected sexual health clinic data.» Sex Transm Infect 93 (2017): 68–70. DOI: 10.1136/sextrans-2016-052553

Ness, R., Kip, K., Hillier, S., et al. «A cluster analysis of bacterial vaginosis-associated microflora and pelvic inflammatory disease.» American Journal of Epidemiology 162.6 (2005): 585–90. DOI: 10.1093/aje/kwi243

Miller, J.M., Binnicker, M.J., Campbell, S., et al. «A Guide to Utilization of the Microbiology Laboratory for Diagnosis of Infectious Diseases: 2018 Update by the Infectious Diseases Society of America and the American Society for Microbiologya.» Clin Infect Dis 67 (2018): 813–6. DOI: 10.1093/cid/ciy584

Chappell, C.A., Wiesenfeld, H.C. «Pathogenesis, diagnosis, and management of severe pelvic inflammatory disease and tuboovarian abscess.» Clin Obstet Gynecol 55 (2012): 893–903. DOI: 10.1097/GRF.0b013e3182714681

MacGowan, A., Macnaughton, E. «Antibiotic resistance.» Med (United Kingdom) 45 (2017): 622–8. DOI: 10.1016/j.mpmed.2017.07.006

Munita, J.M., Arias, C.A. «Mechanisms of Antibiotic Resistance.» In: Virulence Mechanisms of Bacterial Pathogens, 5th Edition. American Society for Microbiology (2016). DOI: 10.1128/9781555819286.CH17

Baylay, A.J., Piddock, L.J.V., Webber, M.A. «Molecular Mechanisms of Antibiotic Resistance – Part I.» In: Bact. Resist. to Antibiot. – From Mol. to Man. John Wiley & Sons Ltd. (2020). DOI: 10.1002/9781119593522

Savaris, R.F., Fuhrich, D.G., Duarte, R.V., et al. «Antibiotic therapy for pelvic inflammatory disease.» Cochrane Database Syst Rev 2017 (2017). DOI: 10.1002/14651858.CD010285.pub2

European Centre for Disease Prevention and Control. Surveillance of antimicrobial resistance in Europe 2017. Available from: [https://www.ecdc.europa.eu/en/publications-data/surveillance-antimicrobial-resistance-europe-2017], last accessed Feb 22, 2020.


GOST Style Citations


1.            Brunham, R.C., Gottlieb, S.L., Paavonen, J. «Pelvic Inflammatory Disease.» N Engl J Med 372 (2015): 2039–48. DOI: 10.1056/NEJMra1411426

2.            Ross, J., Guaschino, S., Cusini, M., Jensen, J. «2017 European guideline for the management of pelvic inflammatory disease.» Int J STD AIDS 29 (2018): 108–14. DOI: 10.1177/0956462417744099

3.            Greydanus, D.E., Bacopoulou, F. «Acute pelvic inflammatory disease.» Pediatr Med 2 (2019): 36. DOI: 10.21037/pm.2019.07.05

4.            Curry, A., Williams, T., Penny, M.L. «Pelvic Inflammatory Disease: Diagnosis, Management, and Prevention.» Am Fam Physician 100 (2019): 357–64.

5.            Das, B.B., Ronda, J., Trent, M. «Pelvic inflammatory disease: Improving awareness, prevention, and treatment.» Infect Drug Resist 9 (2016): 191–7. DOI: 10.2147/IDR.S91260

6.            Moreno, I., Franasiak, J.M. «Endometrial microbiota – new player in town.» Fertil Steril 108 (2017): 32–9. DOI: 10.1016/J.FERTNSTERT.2017.05.034

7.            Khan, K.N., Fujishita, A., Hiraki, K., et al. «Bacterial contamination hypothesis: a new concept in endometriosis.» Reprod Med Biol 17 (2018): 125–33. DOI: 10.1002/rmb2.12083

8.            Tai, F.-W., Chang, C., Chiang, J.-H., et al. «Association of Pelvic Inflammatory Disease with Risk of Endometriosis: A Nationwide Cohort Study Involving 141,460 Individuals.» J Clin Med 7 (2018): 379. DOI: 10.3390/jcm7110379

9.            Stewart, L.M., Stewart, C.J.R., Spilsbury, K., et al. «Association between pelvic inflammatory disease, infertility, ectopic pregnancy and the development of ovarian serous borderline tumor, mucinous borderline tumor and low-grade serous carcinoma.» Gynecol Oncol (2020). DOI:10.1016/j. ygyno.2020.01.027

10.          Zhou, Z., Zeng, F., Yuan, J., et al. «Pelvic inflammatory disease and the risk of ovarian cancer: a meta-analysis.» Cancer Causes Control 28 (2017): 415–28. DOI: 10.1007/s10552-017-0873-3

11.          Frain, A., Fielder, J. «Pelvic inflammatory disease: a review.» O&G Magazine 21.4 (2019). Available from: [https://www.ogmagazine.org.au/21/4-21/pelvic-inflammatory-disease-a-review/], last accessed Feb 22, 2020.

12.          Haque, M. «Antibiotic use, antibiotic resistance, and anti stewardship – a global public consequences.» Bangladesh J Med Sci 18 (2019): 169–70. DOI: 10.3329/bjms.v18i2.40680

13.          Chernick, L.S. «Tubo-Ovarian Abscesses in Nonsexually Active Adolescents: A Rare but Consequential Miss.» J Adolesc Heal 65 (2019): 175–6. DOI: 10.1016/j.jadohealth.2019.04.006

14.          Getahun, A.S., Limaono, J., Ligaitukana, R., et al. «Ovarian abscess caused by Salmonella enterica serovar Typhi: A case report.» J Med Case Rep 13 (2019). DOI: 10.1186/s13256-019-2229-y

15.          Tyan, P., Abi-Khalil, E., Dwarki, K., Moawad, G. «First Described Case of Group B Streptococcus Pelvic Abscess in a Patient with No Medical Comorbidities.» Case Rep Obstet Gynecol 2016 (2016): 1–4. DOI: 10.1155/2016/3724706

16.          Lusby, H., Brooks, A., Hamayoun, E., Finley, A. «Uncommon cause of pelvic inflammatory disease leading to toxic shock syndrome.» BMJ Case Rep 2018 (2018). DOI: 10.1136/bcr-2018-224955

17.          Felz, M.W., Apostol, C.J. «Fatal pneumococcal sepsis from a tuboovarian abscess.» J Am Board Fam Pract 17 (2004): 68–70. DOI: 10.3122/jabfm.17.1.68

18.          Algren, S.D., Strickland, J.L. «Beta hemolytic Streptococcus group F causing pelvic inflammatory disease in a 14-year-old girl.» J Pediatr Adolesc Gynecol 18 (2005): 117–9. DOI: 10.1016/j.jpag.2005.01.007

19.          Yamamoto, T., Kenzaka, T., Mizuki, S., et al. «An extremely rare case of tubo-ovarian abscesses involving corynebacterium striatum as causative agent.» BMC Infect Dis 16 (2016): 1–6. DOI: 10.1186/s12879-016-1860-0

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22.          Okmen, F., Ekici, H., Ari, S.A. «Case Report of a Tubo-ovarian Abscess Caused by Candida kefyr.» J Obstet Gynaecol Canada 40 (2018): 1466–7. DOI: 10.1016/j. jogc.2018.04.025

23.          Trent, M., Bass, D., Ness, R.B., Haggerty, C. «Recurrent PID, subsequent STI, and reproductive health outcomes: Findings from the PID evaluation and clinical health (PEACH) study.» Sex Transm Dis 38 (2011): 879–81. DOI: 10.1097/OLQ.0b013e31821f918c

24.          Safrai, M., Rottenstreich, A., Shushan, A., et al. «Risk factors for recurrent Pelvic Inflammatory Disease.» Eur J Obstet Gynecol Reprod Biol 244 (2020): 40–4. DOI: 10.1016/j. ejogrb.2019.11.004

25.          Sharma, H., Tal, R., Clark, N.A., Segars, J.H. «Microbiota and pelvic inflammatory disease.» Semin Reprod Med 32 (2014): 43–9. DOI: 10.1055/s-0033-1361822

26.          Taylor, B.D., Darville, T., Haggerty, C.L. «Does bacterial vaginosis cause pelvic inflammatory disease?» Sex Transm Dis 40 (2013): 117–22. DOI: 10.1097/OLQ.0b013e31827c5a5b

27.          Centers for Disease Control and Prevention. Pelvic Inflammatory Disease (PID) – 2015 STD Treatment Guidelines. Available from: [https://www.cdc.gov/std/tg2015/pid.htm], last accessed Feb 11, 2020.

28.          Haggerty, C.L. Totten, P.A., Tang, G., et al. «Identification of novel microbes associated with pelvic inflammatory disease and infertility.» Sex Transm Infect 92 (2016): 441–6. DOI: 10.1136/sextrans-2015-052285

29.          Price, M.J., Ades, A.E., Welton, N.J., et al. «Pelvic inflammatory disease and salpingitis: Incidence of primary and repeat episodes in England.» Epidemiol Infect 145 (2017): 208–15. DOI: 10.1017/S0950268816002065

30.          Workowski, K.A., Bolan, G.A. «Centers for Disease Control and Prevention, Sexually transmitted diseases treatment guidelines, 2015.» MMWR Recomm Reports Morb Mortal Wkly Report Recomm Reports 64 (2015): 1–137.

31.          Soper, D.E. Brockwell, N.J., Dalton, H.P., Johnson, D. «Observations concerning the microbial etiology of acute salpingitis.» Am J Obstet Gynecol 170 (1994): 1008–17. DOI: 10.1016/S0002-9378(94)70094-X

32.          Gradison, M. «Pelvic Inflammatory Disease.» Am Fam Physician 85.8 (2012): 791–6.

33.          Price, M.J., Ades, A.E., De Angelis, D., et al. «Risk of pelvic inflammatory disease following chlamydia trachomatis infection: Analysis of prospective studies with a multistate model.» Am J Epidemiol 178 (2013): 484–92. DOI: 10.1093/aje/kws583

34.          Hoenderboom, B.M., Van Benthem, B.H.B., Van Bergen, J.E.A.M., et al. «Relation between Chlamydia trachomatis infection and pelvic inflammatory disease, ectopic pregnancy and tubal factor infertility in a Dutch cohort of women previously tested for chlamydia in a chlamydia screening trial.» Sex Transm Infect 95 (2019): 300–6. DOI: 10.1136/sextrans-2018-053778

35.          Burnett, A.M., Anderson, C.P., Zwank, M.D. «Laboratory-confirmed gonorrhea and/or chlamydia rates in clinically diagnosed pelvic inflammatory disease and cervicitis.» Am J Emerg Med 30 (2012): 1114–7. DOI: 10.1016/J.AJEM.2011.07.014

36.          Jossens, R.M.O., Schachter, J., Sweet, R.L. «Risk Factors Associated With Pelvic Inflammatory Disease of Differing Microbial Etiologies.» Obstet Gynecol 83 (1994): 989–97. DOI: 10.1097/00006250-199406000-00019

37.          Ness, R.B., Soper, D.E., Holley, R.L., et al. «Effectiveness of inpatient and outpatient treatment strategies for women with pelvic inflammatory disease: Results from the Pelvic Inflammatory Disease Evaluation and Clinical Health (PEACH) Randomized Trial.» Am J Obstet Gynecol 186 (2002): 929–37. DOI: 10.1067/mob.2002.121625

38.          Goller, J.L., De Livera, A.M., Fairley, C.K., et al. «Characteristics of pelvic inflammatory disease where no sexually transmitted infection is identified: A cross-sectional analysis of routinely collected sexual health clinic data.» Sex Transm Infect 93 (2017): 68–70. DOI: 10.1136/sextrans-2016-052553

39.          Ness, R., Kip, K., Hillier, S., et al. «A cluster analysis of bacterial vaginosis-associated microflora and pelvic inflammatory disease.» American Journal of Epidemiology 162.6 (2005): 585–90. DOI: 10.1093/aje/kwi243

40.          Miller, J.M., Binnicker, M.J., Campbell, S., et al. «A Guide to Utilization of the Microbiology Laboratory for Diagnosis of Infectious Diseases: 2018 Update by the Infectious Diseases Society of America and the American Society for Microbiologya.» Clin Infect Dis 67 (2018): 813–6. DOI: 10.1093/cid/ciy584

41.          Chappell, C.A., Wiesenfeld, H.C. «Pathogenesis, diagnosis, and management of severe pelvic inflammatory disease and tuboovarian abscess.» Clin Obstet Gynecol 55 (2012): 893–903. DOI: 10.1097/GRF.0b013e3182714681

42.          MacGowan, A., Macnaughton, E. «Antibiotic resistance.» Med (United Kingdom) 45 (2017): 622–8. DOI: 10.1016/j.mpmed.2017.07.006

43.          Munita, J.M., Arias, C.A. «Mechanisms of Antibiotic Resistance.» In: Virulence Mechanisms of Bacterial Pathogens, 5th Edition. American Society for Microbiology (2016). DOI: 10.1128/9781555819286.CH17

44.          Baylay, A.J., Piddock, L.J.V., Webber, M.A. «Molecular Mechanisms of Antibiotic Resistance – Part I.» In: Bact. Resist. to Antibiot. – From Mol. to Man. John Wiley & Sons Ltd. (2020). DOI: 10.1002/9781119593522

45.          Savaris, R.F., Fuhrich, D.G., Duarte, R.V., et al. «Antibiotic therapy for pelvic inflammatory disease.» Cochrane Database Syst Rev 2017 (2017). DOI: 10.1002/14651858.CD010285.pub2

46.          European Centre for Disease Prevention and Control. Surveillance of antimicrobial resistance in Europe 2017. Available from: [https://www.ecdc.europa.eu/en/publications-data/surveillance-antimicrobial-resistance-europe-2017], last accessed Feb 22, 2020.





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