1. ANTIMICROBIAL AGENTS AND PRINCIPLES OF THERAPY Prof T Rogers Clinical Microbiology TCD

2. SOME GENERAL PRINCIPLES Antibiotics can be naturally produced, semi-synthetic, or synthetic substances Designed to have as much selective toxicity on the bacteria as possible This is more likely to be achieved compared to antimicrobials acting against eukaryotic cells (fungi, protozoa)

3. EXAMPLES OF SELECTIVE ACTION Penicillin on bacterial cell wall (organisms without cell wall won’t be inhibited eg Mycoplasma pneumoniae) Sulphonamides prevent bacteria synthesising folic acid whereas humans can use preformed folate Generally drugs acting on cell membranes or protein synthesis are more toxic to humans

5. The Penicillin Molecule

7. ANTIBIOTICS ACTING ON CELL WALL OF BACTERIA BETA LACTAMS: Penicillins, cephalosporins, carbapenems, GLYCOPEPTIDES: Vancomycin, teicoplanin

8. THE IDEAL ANTIBIOTIC?:PENICILLIN Narrow spectrum Bactericidal Very selective mode of action Doesn’t disturb gut flora Low serum protein binding Widely distributed in body esp. CNS Excreted by the kidneys

9. BENZYLPENICILLIN: MAIN INDICATIONS  Strep pyogenes sepsis (from sore throat to fasciitis)  Pneumococcal pneumonia, meningitis  Meningococcal meningitis, sepsis  Infective endocarditis (strep)  Strep group B sepsis  Diphtheria  Syphilis, leptospirosis

10. THE DEVELOPMENT OF THE BETA LACTAMS Benzylpenicillin and early cephalosporins mainly active against gram positive bacteria (strep and staph) Cloxacillin: stable to penicillinase Then “broad spectrum” penicillins appeared: ampicillin, ureidopenicillins and cephalosporins: cefuroxime, cefotaxime Carbapenems and latest generation of cephalosporins, eg ceftazidime more active against gram negatives Monobactam: aztreonam

11. CLOXACILLIN (METICILLIN) Narrow spectrum: Staph aureus (MSSA) Stable to TEM1 beta lactamase Similar antibiotics are meticillin, nafcillin Similar safety profile to benzylpenicillin MRSA emerged in the early 1970’s (MecA gene encoding additional pbp)

12. BROADER SPECTRUM PENICILLINS Ampicillin, amoxycillin cover most organisms hit by penicillin but also Esch coli, some Proteus (cause UTI’s) Augmentin stable to TEM1 beta lactamase because of the clavulanic acid therefore more active than ampicillin Tazocin: broader coverage than augmentin against gram negatives including Pseudomonas

13. PENICILLIN IS GENERALLY VERY SAFE BUT…. Allergic reactions not uncommon-rashes Most severe reaction being anaphylaxis A history of anaphylaxis, urticaria, or rash immediately after penicillin indicates risk of immediate hypersensitivity after a further dose of any penicillin or cephalosporin (therefore these must be avoided) Allergy is not dependent on the dose given ie, a small dose could cause anaphylaxis Very high doses of penicillin can cause neurotoxicity Never give penicillin intrathecally

14. What antibiotics can be used in penicillin allergy? Macrolides: erythromycin, clarithromycin (mainly gram positive cover) Quinolones: ciprofloxacin, levofloxacin (mainly gram positive cover) Glycopeptides (serious infections) Fusidic acid, rifampicin, clindamycin (mainly gram positive)

16. REMEMBER WHAT THE OTHER BETA LACTAMS ARE: All penicillins: ampicillin, augmentin, piperacillin, cloxacillin Cephalosporins: cefuroxime, cefotaxime, ceftriaxone, ceftazidime (5-10% cross sensitivity) Monobactam: aztreonam (low cross sensitivity) Carbapenems: imipenem, meropenem

17. CEPHALOSPORINS: MAIN USES Cefuroxime: surgical prophylaxis Cefotaxime/ceftriaxone: meningitis nosocomial infections excluding Pseudomonal, Ceftazidime: nosocomial infections including those caused by Pseudomonas

18. Problems with antibiotic resistance: how does it happen? Some bacteria are naturally resistant to particular antibiotics (Pseudomonas has permeability barrier to many antibiotics) Some typically susceptible species have minority populations which are resistant by virtue of mutational resistance (pneumococcus) Other species acquire resistance via plasmids (“infectious resistance”) eg Neisseria gonorrhoeae, many gram negatives

20. PENICILLIN RESISTANCE: Organisms producing TEM1beta lactamase Haemophilus influenzae Neisseria gonorrhoeae Bacteroides fragilis Staph aureus Esch coli

21. What are ESBL’s??? Enzymes which have a broad spectrum of activity against third generation cephalosporins eg cefotaxime Can be carried on extrachromosomal plasmids which additionally encode resistance to eg, fluoroquinolones, aminoglycosides Can be spread between different enterobacteria by conjugation As big a threat as MRSA

22. CARBAPENEMS Imipenem, meropenem: have a very broad spectrum activity against gram-negative bacteria, anaerobes, streps Now used to treat gram negative infections due to so called ESBL producing organisms eg, E coli, Klebsiella Ertapenem is a new member of the group but its not active against Pseudomonas

23. A new threat posed by antibiotic resistance: NDM-1 Confer resistance to carbapenems which are among our most efffective antibiotics Pose a new threat Often linked to travel to India but now reported around the World

24. Hospital Healthcare ass’d Community More resistance Less resistance

25. Current major antibiotic resistance problems: community infections Respiratory tract: penicillin resistance in pneumococcus (5-10%) Gastrointestinal: quinolone resistance in Campylobacter Sexually transmitted: penicillin, quinolone resistance in gonococcus Urinary tract: beta lactam resistance in Esch coli Tropical: multidrug resistance in Salmonella typhi, Shigella spp

26. Current major resistance problems: hospital infections MRSA: current strains are often multiply- antibiotic resistant VISA/GISA: intermediate resistance to glycopeptides (thickened cell wall) VRSA/GRSA: highly resistant (transferable on plasmids) from enterococci VRE: enterococci (multiply resistant) Broad spectrum beta lactam resistant (ESBL) and quinolone resistant Esch coli, Klebsiella Multiply antibiotic resistant enterobacteria: Acinetobacter, Stenotrophomonas, Serratia

27. © July Issue of Epi-Insight, Vol 6, Issue 7, Health Protection Surveillance Centre, Ireland

28. S. aureus BSI 2006 COMMUNITYHOSPITAL ACQ’D Cloxacillin

29. MRSAMRSA

31. E. coli - distribution of fluoroquinolone (CIP/OFX) resistance in EARSS countries in 2005

32. EARSS in Ireland – E. coli trends Changes in the numbers of participating laboratories are indicated above the bars

33. TUBERCULOSIS

34. The Threat of Multi-Drug Resistant (MDR) T.B. oHIV patients oErratic or incomplete treatment oNon-compliance oPersistent symptoms despite treatment oResident in area of high prevalence eg, Former Soviet countries

35. Other major antibiotic groups: aminoglycosides Gentamicin, amikacin (tobramycin, streptomycin) Mainly active against gram negative bacteria Mainly used to treat nosocomial infections: pneumonia in ITU, septicaemia Limiting factors are nephrotoxicity (and ototoxicity) and resistance Also used in combination

36. How we give aminoglycosides For serious nosocomial infections: “extended interval” or once daily dosing 5 or 7mg/kg/day for gentamicin (Hartford nomogram) Rationale based on concentration- dependent killing and post-antibiotic effect Reduced risk of nephrotoxicity In infective endocarditis use lower doses to give synergy with penicillin

37. Some other antibiotics occasionally used Co-trimoxazole (Stenotrophomonas) Chloramphenicol (typhoid fever, meningitis) Colistin (resistant Pseudomonas) topical Neomycin: gut decontamination, topical

38. Some indications and limitations of particular antibiotics

39. COMMUNITY ACQUIRED PNEUMONIA: WHAT’S CAUSING IT?

40. TYPICAL GRAM APPEARANCE OF Strep pneumoniae IN SPUTUM GRAM POSITIVE CHAINS DIPLOCOCCI

41. Community acquired pneumonia Pneumococcus (and H influenzae) are most likely: therefore ampicillin, amoxycillin or augmentin Severe pneumonia: cefotaxime Severe atypical pneumonia (Legionella): macrolide or quinolone Resistant pneumococcus: vancomycin or linezolid (new antibiotic!) A new quinolone moxifloxacin covers most of these pathogens (likely to be used more in community)

42. S. pneumoniae *MIC 0.12 -1.0 mg/l **MIC >= 2mg/l

43. Lower Respiratory Tract Infection Antibiotic Guidelines InfectionCommon PathogensRecommended antibiotics (i) Community Acquired Pneumonia S. pneumoniae, H. influenzae, Mycoplasma, Legionella Co-amoxiclav,Clarithromycin (ii) Exacerbation of Chronic Obstructive Pulmonary Disease S. pneumoniae, H. influenzae Moraxella sp. Co-amoxiclav, Moxifloxacin (iii) During influenza epidemicConsider S. aureusFluclox, Vancomycin (iv) Hospital/institutional acquired pneumonia Aerobic Gram-negatives Legionella, S. aureus PipTaz, Cipro gentamicin (v) Aspiration pneumonia a) Community Acquired Aerobic & anaerobic strep b) NosocomialAerobic Gram-negatives

44. Community acquired urinary tract infections Ampicillin, amoxycillin, augmentin Oral cephalosporin: cephradine Trimethroprim Nalidixic acid Nitrofurantoin Ciprofloxacin Mecillinam

45. HA n = 1432 E. coli 605(42%) Enterococcus sp 230(16%) Klebsiella sp. 162(11.3%) P. mirabilis 100(7%) S. aureus 31(2%) HCA n = 562 E. coli 306(54%) Enterococcus sp 87(16%) Klebsiella sp. 50(9%) P. mirabilis 30(5%) P. aeruginosa 14(3%) NHCA n = 870 E. coli 608(70%) Enterococcus sp 67(8%) Klebsiella sp. 40(5%) P. mirabilis 28(3%) Coag neg Staph 25(3%) Top Five URINARY isolates SJH 2006 One isolate per patient included

46. E. coli from Urine

47. Genitourinary infections Antibiotic Guidelines InfectionCommon PathogensRecommended antibiotics Urinary Tract Infection 1. simple cystitis: non- catheter related, non-pregnant women, no prior treatment in community E. coli Other Gram-negative rods Less commonly: Enterococci Staph. saprophyticus Trimethoprim Nitrofurantoin Ciprofloxacin 2. recent treatment or hospitalisedCiprofloxacin 3. Catheter-related Pyelonephritis or Complicated UTI E. coliCiprofloxacin Co-amoxiclav Ceftriaxone IV Gentamicin

48. HA Cipro Resistant E.coli 410 patients with HA Cipro resistant E. coli from 2003 – 2006 29% were Care of the Elderly patients (speciality) 62% were from urine with and w/o catheter

49. Cipro resistance and usage

50. Skin and soft tissue infections Cellulitis ? Streptococcal: penicillin or augmentin Infected eczema ? Staphylococccal/mixed: penicillin+flucloxacillin or augmentin Necrotising fasciitis: penicillin+clindamycin Septic arthritis: fluclox+fusidic acid Gangrene: metronidazole

51. Where there is deep-seated infection: bone, abscess Need an antibiotic with good tissue and phagocyte penetration Examples are rifampicin, clindamycin, fusidic acid, ciprofloxacin, metronidazole So for treatment of Staph aureus osteomyelitis: flucloxacillin+ fusidic acid

52. Why do we use combination therapy? When treating serious infection empirically we want to cover a broad spectrum (severe pneumonia:cefotaxime+erythromycin) To prevent the emergence of drug resistance: tuberculosis regimens For synergy: infective endocarditis (aminoglycoside) For mixed infections eg, abdominal sepsis (tazocin+metronidazole)

53. Are we moving to the Post- antibiotic era? oJudicious use of current antibiotics both in Hospital and Community oNew antibiotics oImprove Infection control practice oBetter management of hospitalised patients

54. New antibiotics Daptomycin: lipopeptide active against strains of Staph aureus (incl MRSA) and VRE (bactericidal) Mode of action: disrupts bacterial cell membrane Given intravenously Indicated for skin and soft tissue infections and R sided endocarditis, bacteraemia due to S aureus Can cause myopathy (monitor CPK weekly)

55. Tigecycline A new glycylcycline antibiotic of tetracycline class Broad spectrum of activity Mode of action: bact. ribosomal synthesis Indicated for skin and soft tissue, and intraabdominal infections Has activity against MRSA, VRE, ESBL producing enterobacteria Monitor liver function

56. Linezolid An oxazolidinone antibiotic Inhibit bacterial protein synthesis Bacteristatic Active against gram positive bacteria incl MRSA and VRE Can be used in pneumonia, skin and soft tissue infections Thrombocytopenia and interactions with SSRI’s 9serotonin release

58. http://www.ndsc.ie/A-Z/MicrobiologyAntimicrobialResistance/EuropeanSurveillanceofAntimicrobialConsumptionESAC/

60. Self assessment: Which one of the following is often resistant to penicillin because of TEM1 encoded penicillinase production: Streptococcus pneumoniae Neisseria meningitidis Streptococcus pyogenes Mycobacterium tuberculosis Neisseria gonorrhoeae

61. Self assessment: which one of the following is not available for oral administration in a case of systemic infection Augmentin Ciprofloxacin Gentamicin Erythromycin Rifampicin

62. Self assessment:Which of the following is a beta lactam antibiotic Clarithromycin Augmentin Nitrofurantoin Nalidixic acid Fusidic acid

63. Self assessment:In a patient with a history of anaphylaxis when previously given penicillin which one of the following should be a safe alternative Clarithromycin Cefuroxime Augmentin Flucloxacillin meropenem