Infectious Diseases Antimicrobial, antibacterial therapy Prof. Elisabeth Nagy Institute of Clinical Microbiology, Uni

1. 1 Infectious DiseasesAntimicrobial, antibacterial therapyProf. Elisabeth Nagy Institute of Clinical Microbiology, University of Szeged Antibiotic selection in different infectious diseases. 6. November 2007

2. 2 Why is the antimicrobial therapy different from therapy with other drugs? Every specialist in medicine use antibiotics The consequences of the inappropriate antibiotic usage is not seen immediately Many patients with infectious diseases can recover without antibiotics Empirical � calculated antibiotic selection Antibiotic therapy guided by in vitro antibiotic resistance determination Laboratory methods to help antibiotic selection

3. 3 Selection of antibiotics for therapy The selection of the antibiotic should depend on the place of the infection the severity of the infection, the general condition of the patient the causative agent the local or regional resistance situation It should be considered the changing spectra of the causative agents Antibiotics should be used only if bacterial infection has been proven or assumed If we give antibiotics, the antibiotic and its doses should be clinical efficacious (�hit and run�).

4. 4 Motto Louis Pasteur: Ce sont les microbes qui auront le dernier mot.

5. 5 It will not be discussed: Antiviral therapy and prophylaxis Antiparasitic therapy and prophylaxis Antibacterial prophylaxis

6. 6 We will discuss: The main classes of antibiotics and their most important characteristics Antibiotic selection in the most important clinical settings (pathogen specific antibiotic selection) Antifungal therapy in systemic fungal infections Laboratory methods to help antibiotic selection

7. 7 Beta-lactam antibiotics The largest group of antibiotics The main features of their antibiotic activity: Slow bactericidal effect, they can have effect on multiplying bacteria Above a given concentration the killing effect can not be increased They have no post-antibiotic effect There is an inoculum's effect (e.g. beta-lactamase producing staphylococci) During therapy the serum concentration of the beta-lactam antibiotics should be kept above the MIC of the pathogen (it should be given in long infusion)

8. 8 Beta-lactam antibiotics Main groups: Penicillines (phenoxymethilpenicillin, benzylpenicillin, ampicillin, amoxicillin flucoloxacillin, methicillin) Cephalosporins (I., II., III., IV. generation) Cephamycins Oxacephems Carbapenems Monobactams Beta-lactam/beta-lactamase inhibitor combinations

9. 9 Beta-lactam antibiotics Their activity: In the bacterial cell they bind to the penicillin binding proteins (target molecules) and inhibit the cell wall production Resistance mechanisms against beta-lactam antibiotics: Production of beta-lactamases (>100 different enzymes). The genes coding the different enzymes can be found on plasmid, on the chromosome, or on transposons Mutation of the penicillin binding proteins (MRSA) Changes in the cell wall permeability (Changes in the efflux pump)

10. 10 Aminoglycosids The classical aminoglycosids: Streptomycin (anti -uberculotic activity) Neomycin (only locally) Kanamycin (is not used because toxicity) Spectinomycin (N. gonorrhoeae) The modern aminoglycosids: Gentamicin Tobramycin Netilmicin Amikacin (Sisomicin, dibecamicin)

11. 11 Aminoglycosides Their activity: Bactericidal antibiotics They are toxic (oto- and nephrotoxicity) In the case of frequent administration they cumulate They inhibit the protein synthesis (binding to the 30s ribosomal protein they inhibit the activity of the mRNS) They have an expressed post-antibiotic activity They can be combined with the beta-lactam antibiotics (synergistic effect) The antibacterial effect is concentration dependent (daily one dose - high peek concentration)

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13. 13 Aminoglycosides Their activity: Bactericidal antibiotics They are toxic (oto- and nephrotoxicity) In the case of frequent administration they cumulate They inhibit the protein synthesis (binding to the 30s ribosomal protein they inhibit the activity of the mRNS) They have an expressed post-antibiotic activity They can be combined with the beta-lactam antibiotics( synergistic effect) The antibacterial effect is concentration dependent (daily one dose - high peek concentration)

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15. 15 Aminoglycosides Their activity: Bactericidal antibiotics They are toxic (oto- and nephrotoxicity) In the case of frequent administration they cumulate They inhibit the protein synthesis (binding to the 30s ribosomal protein they inhibit the activity of the mRNS) They have an expressed post-antibiotic activity They can be combined with the beta-lactam antibiotics (synergistic effect) The antibacterial effect is concentration dependent (daily one dose - high peek concentration)

16. 16 Aminoglycosides Resistance mechanisms: Changes of the target (mutation of the ribosomal proteins) Changes in the permeability of the cell wall (due mutation the active transport of the AGs will be inhibited) Aminoglycoside modifying enzymes (12) (coded on plasmids) 6 modify gentamicin 6 modify tobramycin 4 modify netimicin 2 modify amikacin Active efflux pump function

17. 17 Quinolones - fluoroquinolones They have been in the clinical practice since Quinolones are active against Enterobacteriaceae Fluoroquinolones - have a broader spectrum, especially the 3rd and 4th generation compounds They are bactericidal antibiotics, their activity is dependent from concentration (we had to reach the effective bactericidal activity) AND time dependent (to prevent resistance due to mutation)

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19. 19 Quinolones and fluoroquinolones I. Quinolones : nalidixic acid non complicated urinary tract infection oxolinic acid Fluoroquinolones: 1st gen.: norfloxacine UTI and enteric infections 2nd gen.: pefloxacine as above + chronic ART and LRT ofloxacine infections, HAP, biliary tract inf., ciprofloxacine Go., bon and soft tissue inf.

20. 20 Quinolones and fluoroquinolones II. Fluoroquinolones: 3rd gen.: sparfloxacin CAP, HAP, BAE grepafloxacin intra-abdominal, biliary inf. levofloxacin UTI, pelvic inf., better effect on Gram-positive bacteria 4th gen.: clinafloxacin (trovafloxacin) + anti-anaerobic effect moxifloxacin CAP= community aquiered pneumonia NAP nosocomial aquiered pneumonia BAE Bronchitis acut exacerbatioCAP= community aquiered pneumonia NAP nosocomial aquiered pneumonia BAE Bronchitis acut exacerbatio

21. 21 Activity of quinolones - fluoroquinolones They inhibit the DNA synthesis by inhibiting different enzymes bactericidal effect topoisomerase II (gyrase A, B) Gram-negative bacteria topoisomerase IV parC Gram-positive bacteria As a consequence : the double strand structure of the DNA can not be formed the DNA can not have a place in the cell the single stranded DNA will be split by the endonucleases outside the cell

22. 22 Development of resistance against the fluoroquinolones Due to mutation of chromosomal genes target mutation gyrA, gyrB (Gram-negative bacteria) parC, parE (Gram-positive bacteria) gene mutations responsible for active efflux pump function It has been proved in P. aeruginosa (?15), S. pneumoniae, B. fragilis Mutations of genes responsible for the permeability of the cell wall Plasmid coded resistance has been described

23. 23 Macrolides (azalides) Activity: bacteriostatic drugs (in high concentration and in the case of low inoculum they can be bactericidal) Narrow spectrum - �broad spectrum� Mechanism of the effect: Inhibition of the protein synthesis (they bind to the 50s subunit of the 70s ribosome) Their activity is time dependent, above of certain concentration their activity can not be increased They have a long postantibiotic effect

24. 24 Macrolides (azalides) The classical drugs: erythromycin, oleandomycin Half time: 1,2 h Because of wrong absorption sub-therapeutic level Motilin like effect - diarrhoea New compounds: Better pharmacokinetics (high tissue concentration!!!) No motilin like effect Cross-resistance with the older substances Half life: josamycin (Wilprafen) 1,5 h clarythromycin (Klacid) 3-5 h roxithromycin (Rulid) 8-12 h azithromycin 11-14 h

25. 25 Macrolides are the drug of choice CAP (atypical pneumonia) Mycoplasma pneumoniae, Chlamydia pneumoniae, Legionella pneumophila STDs, pelvic infections Chlamydia trachomatis Haemophylus ducreyi Ureaplasma urealyticum Gastrointestinal infection Campylobacter spp/ Helicobacter pylori Other infections Corynebacterium diphteriae diminish carrier status Borelliosis (Lyme-disease) Mild skin and soft tissue infections

26. 26 Resistance to macrolides Decreased permeability (due to mutation) Production of macrolide splitting enzymes Decreased binding to the receptor (due to mutation) Active efflux The different resistance mechanisms means cross resistance to the different macrolides

27. 27 Lincosamides Lincomycin, clindamycin (Dalacin C) They are active against:- Gram-positive bacteria - anaerobes Excellent penetration to the bones and soft tissue They can be used in case of: Aspiration pneumonia Osteomyelitis In myonecrosis cased by S. pyogenes (in combination with penicillin) Diabetic foot ulcer Bacterial vaginosis as an alternative therapy Resistance mechanisms are the same as in macrolides

28. 28 Tetracyclines The oldest �broad spectrum� antibiotic They are bacteriostatic, they inhibit the protein synthesis of bacteria by binding to the 30s subunit of the ribosome The resistance is spreading very quickly among different bacteria ( the gene can be found on transposons) Active efflux Mutation at the site of the binding of the antibiotic Different derivatives: Older derivatives: oxytetracyclin, chlortetracyclin Newer derivatives: doxycyclin, minocyclin Tygecyclin (introduced recently in clinical practice)

29. 29 Other antibiotics: Chloramphenicol: Broad spectrum, bacteriostatic Inhibit the protein synthesis Toxic (potentially fatal aplastic anaemia) It can be used in special cases: Sever, life threatening mixed infections (aerobic + anaerobic) In meningitis caused by ampicillin resistant H. influenzae Brain abscess (good penetration through the inflamed menings) Severe Salmonella thyphi infection

30. 30 Other antibiotics: Vancomycin / teicoplanin: Bactericidal activity, they inhibit the cell wall synthesis, damage the cytoplasma membrane and inhibit the RNA synthesis High molecular weight glycopeptides They act only on Gram-positive bacteria including: MRSA. MRSE, Enterococcus spp, Corynebacterium JK, D2, Clostridium difficile No cross resistance with beta-lactam antibiotics Synergistic effet with combination of aminoglycosides Resistance appeared in the 1980s (the genes can be found on the chromosome or on plasmids) (vanA, B, C): Enterococci, staphylococci

31. 31 Other antibiotics: Nitroimidazoles: metronidazole, tinidazole Bacteriocidal antibiotics their metabolites damage the bacterial DNA Antiparasitic drug They act on Gram-negative anaerobes, And on some Gram-positive anaerobes (C. difficile) Resistance is rare (Bacteroides spp) Genes which can be found on the chromosome and on plasmids are responsible for the resistance (nimA, B, C, D, E)

32. 32 Other antibiotics: Sulphonamidok, trimetoprim (co-trimoxazol: TMP/SMX 1:20 combination has a synergistic effect) Mupirocin (elimination of carriage of S. aureus, MRSA) Fosfomycin (uncomplicated UTI) Rifampicin (in combination against Gram-positive bacteria) Nitrofurantoin (UTI) Polymyxinek (Colistin) (against pan-resistant pseudomonas inf.)

33. 33 Infectious diseases possible pathogens selection of antibiotics

34. 34 Upper respiratory tract infectionstonsillo-pharyngitis Viruses (80-85%) do not give antibiotics !! S. pyogenes (+ C and G ) penicillin G, (1.,2.g cephalos.) macrolides S. aureus methicillin, (2.g cephalos.), amoxi/clav H. influenzae ampicillin (2., 3.g cephalos.) Vincent angina (anaerobes) amoxi/clav, amp/sulb, clindamycin C. diphtheriae penicillin G, erythromycin (antitoxin) Y. enterocolitica 2.g. cephalosporins M. pneumoniae macrolides (N. meningitidis)* penicillines, macrolides in case of carrige rifampicin/cipro, ceftriaxon Sarjadz� gomba* nystatin (locally) carrige or sign of systemic infection? Penicillin g eset�ben 7 nap cepahlosporinok eset�ben 5 napPenicillin g eset�ben 7 nap cepahlosporinok eset�ben 5 nap

35. 35 Upper respiratory tract infectionsacute sinusitis Dominating flora: H. influenzae (b or other serotype) ? 25% ? S. pneumoniae 35% M. catarrhalis 20% (100%-beta-lactamase producers) Rare pathogens: Other streptococci S. aureus Pseudomonas spp Enterobacteriaceae viruses (rhinovirus, influenza, parainfluenza) (anaerobes) Therapy: ampicillin/amoxicillin, 2., 3. g cephalosporins, beta-lactam/beta-lactamase inhibitor combination, macrolides

36. 36 Upper respiratory tract infectionschronic sinusitis Most frequently isolated bacteria: a-hemolytic streptococci Bacteroides sp H. influenzae Porphyromonas sp S. aureus Fusobacterium sp S. pneumoniae Peptostreptococcus sp M. catarrhalis Peptococcus sp Pseudomonasok V. parvula Klebsiella spp Propionibacterium sp Proteus spp Therapy: antibiotic with an activity against aerobic and anaerobic bacteria (amoxi/clav, combination therapy) Indirect pathogenesity

37. 37 Upper respiratory tract infectionsacut otitis media (AOM) Most frequent pathogens: S. pneumoniae H. influenzae M. catarrhalis (S. aureus (<2%)) (M. pneumoniae) viruses (RSV, influenza, adeno) Therapy: ampicillin/amoxicillin, amoxi/clav, cefaclor, cefuroxim, cefprozil, (pulmonary fluoroquinolones)

38. 38 PneumoniaCommunity acquired pneumonia (CAP) Most frequent pathogens in different age groups: Age group Pathogens New born S. agalactiae C. trachomatis Infants S. pneumoniae H. influenzae b Young adult M. pneumoniae H. influenzae S. aureus Elderly S. pneumoniae Legionella In any age group viruses

39. 39 Pneumoni�kCommunity acquired pneumonia (CAP) Distribution of pathogens according to underlying disease Undelaying disease Possible pathogen COPD S. penumoniae, H. influenzae, Gram- negative rods CF P. aeruginosa, S. aureus HIV P. carinii, atypical mycobacteria Alcoholism S. pneumoniae, H. influenzae, K. pneumoniae Diabetes mellitus S. aureus, mucormycosis

40. 40 PneumoniaTherapy of the community acquired pneumonia (CAP) - Beta-lactam (amoxicillin vagy amoxi/clav. or ceftriaxon) +/- macrolide - New pulmonary fluoroquinolones (moxifloxacin, levofloxacin) - In the case of virus pneumonia antibiotic should be given only as a adjuvant therapy to patients with underlying disease or extreme age

41. 41 Other pneumonia cases Hospital acquired pneumonia (HAP): antibiotic should be given according the antibiogram Aspiration pneumonia: anaerobes can always be involved clindamycin, beta-lactam - beta-lactamase inhibitor combination in severe case carbapenems (cefoxitin / aminoglycoside combination)

42. 42 Acut bronchitis virus infection antibiotic should not be given !! M. pneumoniae macrolide, doxycyclin C. pneumoniae macrolide, doxycyclin S. pneumoniae H. influenzae not always need the antibiotic therapy M. catarrhalis (if yes: pulmonary quinolones moxifloxacin, levofloxacin or amoxi/clav)

43. 43 Chronic bronchitis with acute exacerbation (CBAE) Pathogens: H. influenzae S. pneumoniae M. catarrhalis in rare cases M. pneumoniae Therapy: Amoxi/clav new macrolides (azithromycin) doxycyclin pulmonary fluoroquinolones

44. 44 Gastrointestinal diseases Virus infections: rotavirus in infants and young children) adeno, astro, noro, calici virus, etc. Administration of antibiotics is not recommended !! Bacterial infections: Salmonella sp (fluoroquinolones) Shigella (ampicillin, chloramphenicol) Campylobacter (macrolides) Y. eneterocolitica (if needed according to antibiogram) Vibrio cholerae (tetracyclin) E. coli S. aureus C. difficile (vacomycin ??? metronidazole) Administration of antibiotics is recommended only in sever cases

45. 45 Urinary tract infections Non-complicated UTI: administration of antibiotics p.o. for 3-5 days Sulphametoxasol-trimetoprim Trimetoprim 3 days Fluoroquinolones (1st and 2nd generation) Beta-lactam antibiotikums ampicillin (resistance problems) amoxicillin (resistance problems) Augmentin (amoxicillin/clavul�nsav) 5 days Unasyn (ampicillin/sulbactam) (cephalexin) (cefaclor) One day therapy is not recommended any more!!!

46. 46 UTI (cont.) Non-complicated pyelonephritis Antibiotics should be given parenteral and afterwards p.o. at least for 7-10 days: beta-lactam (2nd gen. cephalosporins, Augmentin, Unasyn) aminoglycosides (gentamycin, tobramycin) After 2 weeks of treatment urine cultuer should be carried out Complicated UTIs Antibiotics should be given parenteral afterwards p.o. for 2-6 weeks (hospitalisation is needed at the beginning of the therapy) Antibiotics should be given according to antibiogram!! Asymptomatic bacteruria � no need of treatment only if the patient is pregnant.

47. 47 Anaerobic infections Frequently mixed infection caused by aerobic and anaerobic bacteria: Aminoglycosid + clindamycin /(cefoxitin) /metronidazol Carbapenems Amoxicillin/clavul�nsav, piperacillin /tazobactam Aminoglycosides are not active against anaerobes Only the 4th gen. Fluoroquinolones have anti-anaerobic effect (clinafloxacin, moxifloxacin)

48. 48 Meningitis Age group Frequent pathogen Other pathogens New born Streptococcus B S. pneumoniae E. coli H. influenzae Listeria spp S. aureus Enterobacteriaceae 1-3 month Streptococcus B E. coli S. pneumoniae Salmonella spp H. influenzae Listeria spp 3 month-5 years S. pneumoniae S. pyogenes H. influenzae Salmonella spp N. meningitidis >5 years S. pneumoniae S. pyogenes N. meningitidis S. aureus

49. 49 Meningitis Empiric therapy: In new born: ceftriaxon/cefotaxim + ampicillin >1 month � 50 years: ceftriaxon/cefotaxim +vancomycin >50 years: (ampicillin) + ceftriaxon/cefotaxim + vancomycin, meropenem Surgery /trauma: ceftazidim + vancomycin, meropenem According to the culture results the empiric therapy should be changed

50. 50 Problematic bacterial strains according to antibiotic resistance Nosocomial multiresistant strains: MRSA MRS cagulase-negative Acinetobacter baumani Pseudomonas aeruginosa Enterococcus faecalis/faecium Enterobacter cloaceae Other problematic strains: - penicillin resistant S. pneumoniae - erythromycin resistant S. pyogenes, S. pneumoniae - fluoroquinolone resistant Gram- negative bacteria - imipenem resistant pseudomonas, B. fragilis - ESBL producing Gram-negative strains - metronidazol resistant Bacteroides - multi-resistant Mycobacterium - etc.

51. 51 Therapy of the systemic fungal infections Special patients population Difficulties in the laboratory diagnosis Most frequent pathogenic fungi

52. 52 Special patient population in risk (systemic fungal infections) Broad spectrum antibiotic therapy Aggressive tumour chemotherapy immunosuppressive therapy immundefficient status for any reason invasive procedures intra-abdominal surgery long-term parenteral nourishing intra-venous and intra-arterial catheters

53. 53 Difficulties in the laboratory diagnosis (systemic fungal infections) The physician should think on it The culture of fungi form the blood in sepsis caused by fungi is successful only in <50% To detect the antigen from the blood is not sensitive enough Molecular genetic methods (PCR) can prove the presence of fungi in genus or species level but can not recover resistance The growth rate is slow Standardisation of the resistance determination is difficult

54. 54 Fugi causing systemic infections Candida albicans Other Candida spp Aspergillus spp Fusarium spp Malassezia spp Trichosporon spp Cryptococcus neoformans Blastoschizomyces capitatum Hansenula anomala Etc.

55. 55 Antifungal drugs used in systemic fungal infection I.

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57. 57 Antifungal drugs used in systemic fungal infection New antifungal drugs are developed they are under clinical investigation (terbinafin, other echinocandins, sordarins, chitin synthetase inhibitors, topoisomerase inhibitors) Antifungal drugs such as antibacterial drugs can be used in combination to increase activity

58. 58 Laboratory methods Disc diffusion method (semi-quantitative S, IM, R) MIC = minimal inhibitory concentration (�break-point�) Antibiotic serum level determination (vancomycin, aminoglycosides) Determination of bactericidal activity in the blood (in case of treatment of endocarditis) Investigation the effect of antibiotic combinations What can we do with the pan-resistant isolates?

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60. 60 Method for detection ESBL production (extended spectrum beta-lactamase)

61. 61 Multiresistant isolates in the clinical practice Citrobacter freundii isolated for the blood culture of a septic patient (only doxycyclin susceptibility)

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63. 63 Strategies how to use antibiotic in severly ill patient The starting antibiotic should have the optimal effect. If the conditions of the patient is improving the antibiotic can be changed (�streamlining�, �step down� therapy) In sever infection such as bacterial sepsis the therapy used in the 24-48 hours will decide the future of the patient and the rate of the lethality!!

64. 64 Erroneous beliefs in connection with the antibiotic therapy The broadest spectrum antibiotic is always the best. The infectious diseases should be treated immediately (we have no time to take samples). The improvement or deterioration of the patient�s condition after introduction of an antibiotic therapy is the sign of the efficacy or ineffectiveness of the selected antibiotic. More sever infection needs more broader spectrum antibiotic treatment. The more sever is the infection the more recently developed antibiotic should be used. The combination of 2 or more antibiotics is more effective than a properly selected single one. The antibiotic which I use will not select antibiotic resistance

65. 65 - SANFORD GUIDE 37th edition (2007) Guide to antimicrobial therapy (ISBN 930808-04-6) Actual national guide lines (evidence based) International guidelines (UK, USA, Canada) Guide lines of the pharmaceutical companies