Antibiotic Update

1. Antibiotic Update

2. Contents • Emerging and reemerging infectious diseases, antibiotic resistance, novel agents and their clinical uses • Reducing bacterial resistance with IMPACT • Antibiotic Stewardship Program (ASP)

3. Penicillins Cephalosporins Carbapenems Quinolones Aminoglycosides Macrolides Tetracyclines Nitrofurantoin, metronidazole, clindamycin, vancomycin, teicoplanin, cotrimoxazole, fusidic acid, etc Isoniazid, pyrazinamide, ethambutol, rifampin, cycloserine, etc Conventional antibiotics

4. Penicillins • Penicillin G • Still useful for a number of diseases (e.g. meningitis, syphilis) • Cloxacillin • For MSSA infections • Ampicillin, amoxicillin • Active vs. Gram-positive (not MSSA), Gram-negative organisms • Augmentin, Unasyn • Broad spectrum, covers Gram-positive, Gram-negative and anaerobes • Piperacillin, Tazocin, Timentin • Are active vs. Pseudomonas

5. Cephalosporins • Cefazolin, cephalexin • Active vs. Gram-positive organisms including MSSA • Cefuroxime, Cefaclor • Covers some Gram-negative organisms • Cefotaxime, Ceftriaxone • Broad spectrum, enhanced activity towards Gram-negative organisms • Ceftazidime, Cefepime, Sulperazon • Additive Pseudomonas coverage

6. Carbapenems • Imipenem • Broad spectrum, covers Gram-positive, Gram-negative (including ESBL-producing strains), Pseudomonas and anaerobes • Meropenem • Less seizure-inducing potential, can be used to treat CNS infections • Ertapenem • Lacks activity vs. Acinetobacter and Pseudomonas • Has limited activity against penicillin-resistant pneumococci

7. Quinolones • Ciprofloxacin • Active vs. MSSA, Gram-negative and Pseudomonas • Levofloxacin • Has activity vs. Streptococcus pneumoniae, but slightly less active towards Pseudomonas compared to ciprofloxacin • Moxifloxacin • Has activity vs. anaerobes but less active towards Pseudomonas

8. Aminoglycosides • Active vs. some Gram-positive and Gram-negative organisms • Gentamicin • Active vs. Pseudomonas • Tobramycin • More active vs. Pseudomonas than gentamicin • Shows less activity against certain other Gram-negative bacteria • Amikacin • More stable to enzymes, used in severe infections by gentamicin-resistant organisms • Streptomycin • Used for tuberculosis

9. Macrolides • Erythromycin • Active vs. Gram-positive organisms, atypicals • GI side effects • Clarithromycin • Slightly greater activity than erythromycin • Azithromycin • Slightly less active than erythromycin vs. Gram-positive but enhanced activity vs. some Gram-negative organisms

10. Tetracyclines • Drug of choice in infections caused by Chlamydia, Rickettsia, Brucella and Lyme disease • Value has decreased due to increasing bacterial resistance • Tetracycline • Role in Helicobacter pylori eradication (less frequently used than other antibiotics) • Doxycycline • Once daily • Minocycline • Broader spectrum

11. Other antibiotics • Clindamycin • Vs. Gram-positive cocci and anaerobes • Metronidazole • Vs. anaerobes • Preferred therapy in antibiotic associated diarrhoea (Clostridium difficile) than oral vancomycin, although unlicenced • Vancomycin, teicoplanin • For Gram-positive organisms (including MRSA)

12. Other antibiotics • Cotrimoxazole • Role in uncomplicated UTI, UTI prophylaxis, acute exacerbations of chronic bronchitis • Pneumocystis carinii (now jiroveci) infections • Nitrofurantoin • For UTI, prophylaxis vs. UTI • Fusidic acid, rifampin • For penicillin-resistant staphylococci • Not for monotherapy due to risk of emergence of resistance

13. Good news vs. bad news • Good news • A few novel antibiotics have shown promising results / are undergoing clinical studies • Bad news • As immunosuppressive diseases and use of immunosuppressive agents become more prevalent, opportunistic infections becomes more common, esp. by organisms rarely encountered previously • Diseases: e.g. HIV, leukemia • Drugs: e.g. in solid organ transplants, bone marrow transplants, rheumatoid disorders • Development of bacterial resistance to antibiotics is much faster than research and development of new antibiotics

14. Emerging and reemerging infectious diseasesAntibiotic resistanceNovel agents and their clinical uses Part 1 Gram-positive superbugs

15. Gram-positive superbugs

16. Case 1 • F/74, DM on oral hypoglycemic drugs • Presented with fever and malaise, cough with sputum, tachypnea; chest X-ray revealed bilateral infiltrates • Travel history, occupation, contact and clustering non-remarkable • Received a course of amoxicillin for urinary tract infection 10 weeks ago • Diagnosis: Community-acquired pneumonia • Question • What is the empirical treatment for CAP?

17. Community-acquired pneumonia (CAP) • Microbiology • “Typical” organisms • Streptococcus pneumoniae • Haemophilus influenzae • Moraxella catarrhalis • “Atypical” organisms • Chlamydia pneumoniae • Mycoplasma pneumoniae • Legionella pneumophilia • Empirical therapy • Beta-lactams to cover typical organisms • Doxycycline / macrolides to cover atypical organisms • Respiratory fluoroquinolones (levo, moxi) for beta-lactam allergy

18. Community-acquired pneumonia (CAP) • Empirical therapy (as per IMPACT) • CAP, out-patient • Augmentin/Unasyn PO ± macrolide PO • Amoxicillin PO + clarithromycin / azithromycin PO • CAP, hospitalized in general ward • Augmentin / Unasyn IV/PO ± macrolide • Cefotaxime / ceftriaxone IV ± macrolide • CAP, hospitalized in ICU for serious disease • Add cover to Gram-negative enterics • Tazocin / cefotaxime / ceftriaxone IV + macrolide • Cefepime IV + macrolide

19. Community-acquired pneumonia (CAP) • Empirical therapy • Modifying factors • Allergy to beta-lactams • Fluoroquinolone (levofloxacin / moxifloxacin) • Aspiration likely: anaerobes should be covered • Augmentin / Unasyn / Tazocin already provide coverage • Cephalosporins (except Sulperazon) is inactive • Moxifloxacin • Bronchiectasis: Pseudomonas cover essential • Tazocin / Timentin / cefepime + macrolide • Fluoroquinolone + aminoglycoside

20. Case 1 • Patient was started on Augmentin + clarithromycin empirically • 3 days later, fever persisted, chest X-ray showed progressive pneumonia • Endotracheal aspirate (WBC +++, few epithelial cells) grew heavy Streptococcus pneumoniae, with penicillin MIC > 4mcg/ml • Questions • Risk factors for penicillin-resistant S. pneumoniae? • Appropriate management in this case?

21. Penicillin resistant Streptococcus pneumoniae(PRSP) • Risk factors • Age > 65 years • Beta-lactam therapy in past 3 months • Alcoholism • Multiple medical comorbidities (e.g. immunosuppressive illness or medications) • Exposure to a child in a day care centre

22. Penicillin resistant Streptococcus pneumoniae(PRSP) • If susceptible, penicillin group is the drug of choice for Streptococcus pneumoniae • Check susceptibility and MIC if resistant to penicillin • Penicillin susceptible (MIC  0.1 mcg/ml) • Penicillin G, amoxicillin • Penicillin resistant (0.1< MIC 1.0 mcg/ml) • High dose penicillin G or ampicillin, cefotaxime / ceftriaxone

23. Penicillin resistant Streptococcus pneumoniae(PRSP) • Penicillin resistant (MIC > 2.0 mcg/ml) • Vancomycin  rifampin • High dose cefotaxime tried in meningitis • Non-meningeal infection: cefotaxime / ceftriaxone, high dose ampicillin, carbapenems, or fluoroquinolone (levofloxacin, moxifloxacin) • Multidrug resistant (MDRSP, resistant to any 2 of the following: penicillins, erythromycin, tetracycline, macrolides, cotrimoxazole) • Vancomycin  rifampin • Clindamycin, levofloxacin, moxifloxacin could be tried

24. Penicillin resistant Streptococcus pneumoniae(PRSP) • Any alternative for PRSP / MDRSP in respiratory tract infection? • Newer agents • Telithromycin (Ketek®) • Linezolid (Zyvox®)

25. Telithromycin (Ketek®) • A ketolide (structurally related to macrolides) • Spectrum of activity • Group A, B, C and G Streptococci, Streptococcus pneumoniae (including multidrug resistant strains), MSSA • Listeria monocytogenes, Neisseria meningitidis, Moraxella catarrhalis, Haemophilus influenzae • Legionella, Chlamydia, Mycoplasma • No activity vs. MRSA, GRE, or any enteric gram-negative bacteria • Indications • Mild to moderate community acquired pneumonia

26. Linezolid (Zyvox®) • An oxazolidinedione • Spectrum of activity and indications • Vancomycin-Resistant Enterococcus faeciuminfections, including cases with concurrent bacteremia • Nosocomial pneumonia caused by MSSA or MRSA or Strep pneumoniae (including MDRSP) • Complicated skin and skin structure infections, including diabetic foot infections, without concomitant osteomyelitis, caused by MSSA or MRSA, Strep pyogenes, or Strep agalactiae • Uncomplicated skin and skin structure infectionscaused by MSSA or Strep pyogenes. • Community-acquired pneumoniacaused by Strep pneumoniae (including MDRSP), including cases with concurrent bacteremia, or MSSA

27. Case 2 • M/56 • Presented with skin redness, warmth, swelling, tenderness on his right lower limb, a pocket of fluid palpated • Diagnosis: cellulitis with pus formation • Question • Empirical treatment?

28. Skin and soft tissue infection • Cellulitis • Microbiology • Staphylococcus, Streptococci • Streptococci more likely when cellulitis is well demarcated and there are no pockets of pus or evidence of vein thrombosis

29. Staphylococcus aureus • If susceptible, penicillinase-resistant penicillins are the drugs of choice for methicillin-susceptible Staphylococcus aureus (MSSA) • Drug of choice • Cloxacillin, flucloxacillin • Cefazolin, cephalexin (penicillin allergic but tolerate cephs) • With beta-lactamase inhibitor • As two-agent combination in Augmentin, Unasyn • Erythromycin, clindamycin (if penicillin allergic) • The above antibiotics also have good activity vs. Streptococci

30. Case 2 • Skin tenderness and redness did not appear to improve despite Augmentin has been given • Pus grew MRSA after 2 days • R to methicillin, cephalothin, erythromycin • S to clindamycin, vancomycin, gentamicin, cotrimoxazole • Patient is clinically stable • Questions • What is the drug of choice in MRSA infection? • Can clindamycin be used in this case?

31. Healthcare-associated Endemic in hospitals, old age homes Risk factors Hospitalization in previous 1 year Recent surgery Old age home residence Renal dialysis Exposure to invasive devices Employment in a healthcare institute Community-associated Do not have usual risk factors associated with HA-MRSA More common in the following in overseas countries Children with chronic skin condition Prisoners Military personnel Aboriginals Injection drug users The homeless Contact sports athletes Methicillin resistant Staphylococcus aureus(MRSA)

32. Healthcare-associated Multiresistant to Clindamycin Aminoglycosides Tetracyclines Fluoroquinolones Community-associated Often remains susceptible to Clindamycin Aminoglycosides Tetracyclines Fluoroquinolones More associated with skin/soft tissue infections and severe necrotizing pneumonia Methicillin resistant Staphylococcus aureus(MRSA)

33. Methicillin resistant Staphylococcus aureus(MRSA) • Obtain culture for susceptibility testing right before empirical antibiotics! • Treatment (as per Sanford Guide 37th ed) • Community-associated • Mild to moderate infections • Abscess, afebrile, immunocompetent, outpatient • Cotrimoxazole / doxycycline / minocycline  rifampin • Clindamycin (do not use if R to erythromycin due to inducible resistance) • Abscess with fever, outpatient • Cotrimoxazole-DS + rifampin or linezolid

34. Methicillin resistant Staphylococcus aureus(MRSA) • Clinical guideline for management of suspected CA-MRSA infections (15 March 2007) • Most CA-MRSA isolates in HKSAR are susceptible to: • Cotrimoxazole • Doxycycline, minocycline • Clindamycin • Moxifloxacin • Out-patient oral therapy available for uncomplicated CA-MRSA skin and soft tissue infection

35. Methicillin resistant Staphylococcus aureus(MRSA)

36. Methicillin resistant Staphylococcus aureus(MRSA) • Appropriate treatment in uncomplicated skin and soft tissue infection • Cotrimoxazole, doxycycline, minocycline or moxifloxacin • Clindamycin is not reliable in this case • Inducible clindamycin resistance due to erythromycin resistance

37. Case 2 • What to do if • the organism is resistant to agents listed above and vancomycin, and • Infection is complicated (unstable patient, extensive involvement, severe sepsis, etc)?

38. VISA and VRSA • VISA: vancomycin-intermediate Staph aureus • VRSA: vancomycin-resistant Staph aureus • Classified based on minimum inhibitory concentration (MIC) • (CDC definition) • VISA: vancomycin MIC is 4-8 µg/ml • VRSA: vancomycin MIC is >16 µg/ml • (HA Central Committee on Infectious Diseases) • Susceptible: vancomycin MIC is ≤ 4µg/ml • VISA: vancomycin MIC is 8-16 µg/ml • VRSA: vancomycin MIC is >32 µg/ml

39. VISA and VRSA • More likely to develop among patients with • Underlying conditions (including renal failure) which predispose the patient to MRSA colonization; • Indwelling medical devices; and/or • MRSA infection requiring treatment with vancomycin for a prolonged period • Usually isolated during vancomycin (or teicoplanin) therapy for MRSA infections which fail to respond

40. VISA and VRSA • Linezolid (Zyvox®) • (discussed in PRSP session) • Quinupristin/dalfopristin (Synercid®) • Dalbavancin (Zeven®) • Still under investigation • Daptomycin (Cubicin®) • Tigecycline (Tygacil®)

41. Linezolid (Zyvox®) • Demonstrate bacteriostatic action vs. VISA and VRSA • Indications • Complicated skin and skin structure infections, including diabetic foot infections, without concomitant osteomyelitis, caused by MSSA or MRSA, Strep pyogenes, or Strep agalactiae • Uncomplicated skin and skin structure infectionscaused by MSSA or Strep pyogenes

42. Quinupristin/dalfopristin (Synercid®) • Intravenous streptogramins (combination results in synergy) • In vitro activity has been demonstrated against VISA and VRSA • Spectrum of activity • Vancomycin-resistant Enterococcus faecium • Penicillin-resistant Streptococcus pneumoniae • Methicillin-resistant Staphylococci • Vancomycin-resistant Enterococcus faecalis is relatively resistant to quinopristin/dalfopristin • Anaerobes and some gram-negative pathogens (e.g., Haemophilus influenzae) have also been susceptible • Indications • Bacteremia - Vancomycin-resistant Enterococcus faecium infection • Infection of skin and/or subcutaneous tissue, Complicated, causedby Staphylococcus aureus and Streptococcus pyogenes

43. Dalbavancin (Zeven®) • Second generation glycopeptide • First generation: vancomycin, teicoplanin • Spectrum of activity • Staphylococci and Streptococci, including resistant isolates • Clostridium spp., Peptostreptococcus spp., Actiniomyces spp., Corynebacterium spp. and Bacillus subtilis • No activity vs. most gram-negative bacteria • No activity vs. vancomycin-resistant enterococci with Van A gene

44. Dalbavancin (Zeven®) • Demonstrated favorable in vitro activity against MSSA, MRSA,VISA, VRSA, and linezolid-resistant S. aureus • Also, methicillin-susceptible, methicillin-resistant, and vancomycin-intermediate Coagulase negative Staphylococci strains have had favorable in vitro results • Place of therapy (no FDA approved indication at the moment) • Currently in phase III trials for treatment of resistant gram-positive organisms • Published efficacy and safety data from 2 clinical trials are available for treatment of skin and soft-tissue infections and catheter-related bloodstream infections

45. Daptomycin (Cubicin®) • Cyclic lipoglycopeptide • Spectrum of activity • MSSA, MRSA, Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus dysgalactiae subsp. equisimilis, and • Enterococcus faecalis (vancomycin-susceptible isolates only) • Indications • Complicated skin and skin structure infectionscaused by susceptible Gram-positive microorganisms • Staphylococcus aureus bloodstream infections including those with right-sided infective endocarditis (methicillin-susceptible and methicillin-resistant) (native valve)

46. Tigecycline (Tygacil®) • A glycylcycline • Derived from minocycline • A very broad spectrum antibiotic • Covers many resistant strains of Gram-positive, Gram-negative, and anaerobic organisms • Note active vs. Pseudomonas • Both in vitro and in vivo activities have been demonstrated against MSSA, MRSA, and VISA

47. Indications Complicated skin and skin structure infections by Escherichia coli Enterococcus faecalis (vancomycin-susceptible isolates only) Staphylococcus aureus (Methi-S or Methi-R) Streptococcus agalactiae Streptococcus anginosus grp. Streptococcus pyogenes Bacteroides fragilis Complicated intra-abdominal infections by Citrobacter freundii Enterobacter cloacae E. coli, K. oxytoca, K. pneumoniae Enterococcus faecalis (Vanco-S isolates only) Staphylococcus aureus (Methi-S or Methi-R) Streptococcus anginosus group Bacteriodes fragilis Clostridium perfringens Peptostreptococcus micros Tigecycline (Tygacil®)

48. Emerging and reemerging infectious diseasesAntibiotic resistanceNovel agents and their clinical uses Part 2 Gram-negative superbugs

49. Gram-negative superbugs

50. Case 3 • M/59 • Presented with 2-day history of right upper quadrant pain, fever, jaundice • Emesis x 2 past 24 hours, dark color urine • Elevated LFT • Radiologic finding: dilated common bile duct, no increase in gallbladder size • Diagnosis: acute cholangitis • Question • What is the empirical therapy?