ESCMID Online Lecture Library. by author

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1 Anaerobic infections: antibiotic therapy and development of resistance Inge C Gyssens 1 0ctober 2014

2 Objectives To review the clinical aspects of some anaerobic infections To understand the epidemiology of resistance of anaerobic bacteria To discuss two clinical cases of infection on 2 different anatomical sites To choose appropriate therapy from the arsenal of old and new antibiotics

3 Pathogenesis: the bacteria and the host

4 Pathogenesis of anaerobic infections Bacterial contamination x Virulence = Risk of Host defense Infection

5 Characteristics of anaerobic bacteria Virulence: endotoxin Synergy in «mixed infection» E. coli and B. fragilis Streptococci and B. fragilis Enterococci and B. fragilis Anaerobic gram positive cocci Pus: Abscess formation

6 Bacteroides fragilis cell envelope Polysaccharide capsule is involved in abscess formation

7 Fusobacterium sp virulence factors Lipopolysaccharide endotoxin capable of causing an intense systemic sepsis. Haemolysin, contributing to abscess formation Haemagglutinin, of which the relevance to pathogenesis of human infection is uncertain Fimbrae for adhesion to host cells Capability to cause platelet aggregation, which may help to promote a favourable anaerobic environment for survival of the organism in abscesses Synergy with other bacteria (Group C streptococci) /viruses (EBV)

8 Host factors Age Site of infection Impaired immunity Adapted immunity Polymorphonuclear leukocytes T lymphocytes Innate immunity (research)

9 Innate immunity pathways Trinchieri G, Sher A. Nat Rev Immunol. 2007; 7(3):

10 Cytokine profile induced by B. fragilis Concentration (pg/ml) Stappers et al. Cytokine 2012 *** RPMI B. fragilis S. aureus *** *** *** *** IL-1 IL-6 IL-8 IL-17 TNF- n: (RPMI) (Bf) (Sa) ***: p<0.0001

11 SNPs in NOD2 reduce B. fragilis induced cytokine production M Stappers et al. Cytokine 2012

12 Clinical aspects of anaerobic infections

13 Clinical disease varies according to site A. Skin and skin structure infections Necrotising fasciitis Gas gangrene Diabetic foot B. Perforation of the gastrointestinal tract Head & Neck infections Parodontal infections Peritonsillar or retropharyngeal abscess following tonsillitis Lemierre Syndrome Mediastinitis Actinomycosis Abdominal sepsis Pseudomembranous colitis (Uro)- anogenital infections.. With or without abscess formation

14 Anaerobic infections A. Skin and skin structure infections Necrotising fasciitis Gas gangrene Diabetic foot

15 Anatomy of Skin and Skin structure infections From: P. Kujath. Haut- und Weichgewebsinktionen, UNI-MED, 2004, Bremen

16 Clinical aspects of deep abscesses Antibiotics have impaired activity in well formed abscesses Drainage is required in most cases Factors influencing the activity of antibiotics: low oxygen content (anaerobic milieu) low ph in the abscess

17 csssi Most frequent pathogens Staphylococcus aureus Streptococci but

18 Pathogens encountered in csssi studies Tan et al, AAC 1993 Graham et al, CID 2003

19 Necrotising fasciitis

20 Treatment of csssi Principles Optimal antibiotic regimen but Sufficient and rapid surgical debridement

21 Diabetic foot ulcer infection The major risk factor for severe infection is peripheral arterial disease The Eurodiale study Prompers et al.

22 433 patients 427 positive cultures; 83% polymicrobial, 48% only aerobes 43,7% both aerobes and anaerobes, 1,3% only anaerobes. Cultures yielded a total of 1145 aerobic and 462 anaerobic strains, with an average of 2.7 organisms (range 1 to 8) for aerobes and 2.3 organisms per culture (range 1 to 9) for anaerobes

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24 Bacteroides spp resistance percentages, range United States Snydman Anaerobe 2011 Spain Trevino Anaerobe 2012 Taiwan Liu AAC 2008 blood N Zealand Roberts JAC 2006 Belgium Wybo JAC 2014 N=1957 N =1343 N=113 N=100 N= 180 metronidazole 1+1 isolate clindamycin coamoxiclav NA cefoxitin NA moxifloxacin NA 38 tigecycline NA NA NA piperacillin/tazobactam NA imipenem/meropenem/ ertapenem / /2-4 8 chloramphenicol NA 3

25 Diabetic foot infection in hospital: therapy No previous antibiotics, no severe peripheral arterial disease: Amoxicillin clavulanic acid iv Switch to clindamycin orally or flucloxacillin if culture shows gram positive pathogens Previous antibiotics, severe peripheral arterial disease Piperacillin tazobactam Carbapenem.. Switch to fluoroquinolone and clindamycin orally guided by culture data

26 Clinical entities vary according to site B. Perforation of the digestive tract Head & Neck infections Parodontal infections Retropharyngeal peritonsillar abscess following tonsillitis Lemierre Syndrome Mediastinitis Actinomycosis Abdominal sepsis Pseudomembranous colitis (Uro)- anogenital infections.. with or without abscess formation

27 ischiorectal abscess Skin flora or bowel flora? King M, Ed. Primary surgery vol 1 Non-trauma. Oxford University Press, Oxford, 2003

28 ! Essential treatment component: Surgical debridement From: P. Kujath. Haut- und Weichgewebsinktionen, UNI-MED, 2004, Bremen

29 Diagnostics Imaging Sample collection Laboratory Identification and susceptibility

30 Routine anaerobic blood cultures, yes or no? Lassman et al. Clin Infect Dis 2007 Editorial by Hecht Clin Infect Dis 2007 It seems less predictable than it used to be when anaerobic pathogens play a role

31 Antibacterials active against anaerobes Beta-lactams Interfere with cell wall synthesis: penicillins /+ betalactamase inhibitors, amoxicillin clavulanic acid, piperacillin tazobactam, cefalosporins Protein synthesis inhibitors (antiribosomal antibiotics): clindamycin, tigecycline Inhibitors of DNA synthesis gyrase/topoisomerase II: newer quinolones metronidazole

32 Interpreting surveillance susceptibility data Wybo et al 2014

33 Case 1 A boy with a painful swelling of the neck 17-year old boy has returned home from a summer camp 2 days ago. He has fever 38.9 C and severe pain on the left side of his neck. He was prescribed oral amoxicillin clavulanic acid by his GP on the first day of his return but today he has vomited and is sent to the emergency department. On examination he has a very painful bulging swelling on the left side of his neck.

34 Case 1 A boy with a painful swelling of the neck Q1 What is your differential diagnosis? Q2 Which laboratory tests should be performed? Q3 Imaging?

35 A life-threatening sore throat masquerading as swine flu Kahr et al, Lancet 2010 February 375: 524 Left : Absence of contrast within proximal left internal jugular vein indicates thrombosis. Right: Complete opacification of the middle ear cleft with further soft tissue within the external auditory canal.

36 Case 1 A boy with a painful swelling of the neck At drainage, the surgeon only requested aerobic cultures of the pus, which yielded no growth. However, from the enrichment medium Fusobacterium necrophorum was grown and reported after 3 days

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38 Treating infections caused by Fusobacterium necrophorum and spp., resistance percentages, range UK Brazier Anaerobe 2006 Taiwan Liu AAC 2008 blood Netherlands Veloo Anaerobe 2014 Belgium Wybo Anaerobe 2014 N= 100 N = 27 N = 39 N = 21 penicillin/amoxicillin 2 11 /15 19 metronidazole clindamycin coamoxiclav cefoxitin 0 NA 0 0 erythromycin 15 NA NA NA tetracycline 1 NA NA NA moxifloxacin NA 0 NA 29 piperacillin/tazobactam NA 0 NA 0 imipenem/meropenem 0 4/8 NA 0 chloramphenicol 0 4 NA 0

39 Case 2 Intraabdominal abscess following intestinal perforation Case A 58 year old man, mr F., is diagnosed with lung carcinoma T4 N2 M0 (stage IIIb). He is treated with three-weekly courses of cisplatin/ etoposide and gemcitabine. Side effects consist of severe constipation. Two months later, after three courses of chemotherapy, he is readmitted with a history of worsening constipation and abdominal pain. On physical examination paralytic ileus is suspected. The next day his temperature is 38.5 C and the nurses draw blood cultures. One day later, symptoms become more severe and a plain X-Ray of the abdomen is compatible with intestinal perforation. This is confirmed by laparotomy. There is faecal spill in the abdominal cavity. Secundary peritonitis is diagnosed.

40 Case 2 Intraabdominal abscess following intestinal perforation Q1 What would be the empirical antimicrobial regimen in your hospital? Sources: - - antibiotic guide of your hospital - national antibiotic guidelines

41 Antibiotic therapy for secondary peritonitis, NL ceftriaxone iv 2000mg 1dd +metronidazole iv 500mg 3dd 5 to 14 days + aminoglycoside iv 1dd cefotaxime iv 1000mg 4dd + metronidazole iv 500mg 3dd 5 to 14 days + aminoglycoside iv 1dd cefuroxime iv 1500mg 3dd + metronidazole iv 500mg 3dd 5 to 14 days + aminoglycoside iv 1dd amoxicillin iv 1000mg 4dd + metronidazole iv 500mg 3dd 5 to 14 days + aminoglycoside iv 1dd amoxicillin + clavulanic acid iv 1000/200mg 4dd 5 to 14 days + aminoglycoside iv 1dd

42 Case 2 Intraabdominal abscess following intestinal perforation Case continued The surgeon has prescribed amoxicillin clavulanic acid, 1000/200 mg iv four times daily. On the next day, the anaerobic bottles of 2 pairs of blood cultures grow gram negative bacillae, identified as Bacteroides stercoris.

43 Case 2 Intraabdominal abscess following intestinal perforation Q2 Should susceptibility testing be performed? Q3 Which antimicrobials should be tested? Q4 Would you change the antibiotic regimen? (antibiotic, schedule, duration)

44 Case 2 Intraabdominal abscess following intestinal perforation Case continued Six days later, the temperature is 39 C. Mr. F. is still treated with amoxicillin clavulanic acid. He complains of right flank pain. The abdomen is tender on palpation. Susceptibility testing reveals intermediary resistance (I) to amoxicillin clavulanic acid. A CT scan of the abdomen shows several paracolic fluid collections, suggestive of abscess formation. The patient has clinical sepsis. A relaparotomy is performed. Pus from two large abscesses is drained and the surgeon calls you for advice.

45 Case 2 Intraabdominal abscess following intestinal perforation Q5 What is your advice on laboratory diagnostics and antimicrobial therapy now?

46 MIC 50, MIC 90 and Resistance of anaerobes in the Netherlands

47 Case 2 Intraabdominal abscess following intestinal perforation After 2 days, two different anaerobe gram negative rods are cultured from the drained pus. Q6 Should susceptibility testing be performed? Q7 What is your advice on antimicrobial therapy?

48 Bacteroides spp resistance percentages, range United States Snydman Anaerobe 2011 Spain Trevino Anaerobe 2012 Taiwan Liu AAC 2008 blood N Zealand Roberts JAC 2006 Belgium Wybo JAC 2014 N=1957 N =1343 N=113 N=100 N= 180 metronidazole 1+1 isolate clindamycin coamoxiclav NA cefoxitin NA moxifloxacin NA 38 tigecycline NA NA NA piperacillin/tazobactam NA imipenem/meropenem/ ertapenem / /2-4 8 chloramphenicol NA 3

49 Lofmark et al

50 Snydman et al Anaerobe 2011

51 Conclusion Which antibiotic to select for anaerobic infections? Empirical therapy Beta lactamase inhibitors: amoxicillin clavulanic acid, piperacillin tazobactam Cefuroxime or ceftriaxone + metronidazole Carbapenems: imipenem, meropenem, ertapenem (Tigecycline) Definitive therapy : «narrow spectrum» Penicillin Metronidazole Clindamycin Newer quinolones: moxifloxacin.