This document discusses various antibiotics, their uses, and emerging issues with antibiotic resistance. It provides guidance on empiric treatment for common infections like community-acquired pneumonia and skin/soft tissue infections. For a case of community-acquired pneumonia, the patient was initially treated empirically with Augmentin and clarithromycin per guidelines. Testing later found penicillin-resistant Streptococcus pneumoniae, requiring a change to higher dose beta-lactams, vancomycin, or fluoroquinolones. A case of cellulitis grew methicillin-resistant Staphylococcus aureus despite initial Augmentin treatment. The drug of choice for MRSA is vancomycin,

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

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 diseases Antibiotic resistance Novel agents and their clinical uses Part 1 Gram-positive superbugs

15. Gram-positive superbugs Resistant Gram-positive bacteria terminology PRSP Penicillin resistant Streptococcus pneumoniae MDRSP Multidrug resistant Streptococcus pneumoniae MRSA Methicillin resistant Staphylococcus aureus VRSA Vancomycin resistant Staphylococcus aureus VISA (GISA) Vancomycin (Glycopeptide) intermediate Staphylococcus aureus VRE (GRE) Vancomycin (Glycopeptide) resistant Enterococcus

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 i ndications Vancomycin-Resistant Enterococcus faecium infections , 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 infections caused by MSSA or Strep pyogenes. Community-acquired pneumonia caused 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. Methicillin resistant Staphylococcus aureus (MRSA) 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

32. Methicillin resistant Staphylococcus aureus (MRSA) 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

33. Methicillin resistant Staphylococcus aureus (MRSA) Obtain culture for susceptibility testing right before empirical antibiotics! Treatment (as per Sanford Guide 37 th 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) Antimicrobials for outpatient therapy of uncomplicated skin and soft tissue infections (Clinical guideline for management of suspected CA-MRSA infections,15 March 2007) Agent Potential advantage Precautions Usual adult dose (oral) Cotrimoxazole Oral Not for patient with sulfa allergy / G6PD 960mg bd Doxycycline High skin concentration Not for children <12 yo or pregnant women 200mg once, then 100mg bd Minocycline As above As above 100mg bd Clindamycin Inhibit toxin production Inducible resistance if erythromycin resistant 300-450mg tds Moxifloxacin Oral Resistance may develop during therapy 400mg qd

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 infections caused 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, caused by 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 infections caused 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. Tigecycline (Tygacil®) 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

48. Emerging and reemerging infectious diseases Antibiotic resistance Novel agents and their clinical uses Part 2 Gram-negative superbugs

49. Gram-negative superbugs Resistant Gram-negative bacteria terminology ESBL-producing Enterobacteriaceae Extended spectrum beta-lactamases producing Enterobacteriaceae, e.g. Escherichia coli, Klebsiella pneumoniae MRPA (MDR-PA) Multidrug resistant Pseudomonas aeruginosa MRAB (MDR-AB) Multidrug resistant Acinetobacter baumannii Pan-resistant Pseudomonas aeruginosa / Acinetobacter baumannii

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?

51. Acute cholangitis/cholecystitis Microbiology Gram negative enterics E. coli, Klebsiella spp., Proteus spp. Anerobes Bacteriodes fragilis, Clostridium spp. Enterococcus

52. Acute cholangitis/cholecystitis Adequate drainage is essential Empirical treatment complementary to drainage Augmentin/Unasyn ± aminoglycoside Timentin Cefuroxime + metronidazole Ciprofloxacin (if beta-lactam allergic)

53. Case 3 Biliary drainage performed with cefuroxime + metronidazole pre- and post-operation Became septic (with high fever, tachycardia, WBC > 12 x 10 9 /L) 2 days post-op Blood culture grew E. coli (ESBL-producing), moderately sensitive to Augmentin, sensitive to Sulperazon and imipenem Question What is the appropriate treatment? Can Augmentin or Sulperazon be used?

54. Enterobacteriaceae Susceptible strains of E. coli and Klebsiella are sensitive to Augmentin/Unasyn Cefuroxime (if resistant to above) Other anti gram-negative penicillins/cephs also work Fluoroquinolones (if allergic to beta-lactams)

55. ESBL-producing Enterobacteriaceae Extended-spectrum beta-lactamases Any bacterial enzymes that are capable of inactivating third generation cephalosporins Generally regarded as resistant to penicillins and cephalosporins Drug of choice Urinary tract infection Cotrimoxazole, Augmentin, nitrofurantoin, levofloxacin / ciprofloxain Other serious infections Carbapenems: imipenem, meropenem, ertapenem (reliable activity vs. ESBL-producing Enterobacteriaceae) Fluoroquinolone + aminoglycoside

56. Case 3 Augmentin and Sulperazon are not appropriate Patient is clinically septic (likely due to the ESBL-producing strain of E. coli) The strain is only apparently susceptible to the above agents Appropriate agent Ertapenem (no activity vs. Pseudomonas) Imipenem (when activity vs. Pseudomonas required)

57. Case 4 M/33 Victim of road traffic accident Experienced severe burns during accident Early excision and repair performed; silver sulfadiazine cream topically High fever on day 5, blood culture grew Pseudomonas aeruginosa on day 7 Question Appropriate known pathogen therapy?

58. Pseudomonas aeruginosa Gram-negative bacilli Frequently present in small numbers in the normal intestinal flora and on the skin of humans and is the major pathogen Causes diseases in patients with abnormal host defenses, e.g. When mucous membranes and skin are disrupted When intravenous or urinary catheters are used When neutropenia is present (as in chemotherapy) Intrinsically resistant to many antibiotics

59. Pseudomonas aeruginosa Drug of choice Antipseudomonal penicillins/cephalosporins Piperacillin, piperacillin/tazobactam (Tazocin), ticarcillin/clavulanate (Timentin) Ceftazidime, cefoperazone, cefepime Carbapenems Imipenem, meropenem (NOT ertapenem) Aminoglycosides Gentamicin, tobramycin, amikacin Fluoroquinolones Ciprofloxacin, levofloxacin (less activity than cipro) Often a two-drug combination is employed except in uncomplicated UTI

60. Case 4 Tazocin (Piperacillin/tazobactam) plus gentamicin were prescribed Microbiologist suggested using piperacillin plus gentamicin is sufficient for this patient Question What is the difference in activities (and hence uses) between Tazocin and piperacillin?

61. Piperacillin vs. Tazocin Tazobactam in Tazocin® Tazobactam is a beta-lactamase inhibitor Renders the combination of Tazocin® more active against Gram positive: MSSA Gram negative: Haemophilus influenzae and others Anaerobe: Bacteroides fragilis

62. Piperacillin vs. Tazocin Tazobactam in Tazocin® For Pseudomonas aeruginosa susceptible to piperacillin, Tazocin 4.5g Q8H IV and Piperacillin 4g Q8H IV are equivalent At common usual dose (HA Corp drug price as of May 2007) Piperacillin 4g/vial: $56 Tazocin® 4.5g/vial: $108

63. Multidrug resistant Gram-negative organisms Any treatment options for ESBL-producing Enterobacteriaceae, or Pseudomonas aeruginosa, that are pan-resistant?

64. Colistin (Colomycin®) Indeed an old, toxic drug! a.k.a. Polymyxin E, colistimethate sodium Now being used with increasing frequency due to necessity (multidrug resistant Gram-negatives) Risk of neurotoxicity and nephrotoxicity Spectrum of activity (check susceptibility!) Pseudomonas aeruginosa, Acinetobacter spp. E. coli and Klebsiella (incl. ESBL-producing strains), Enterobacter spp. Citrobacter spp, Hemophilus spp. Indications Disease due to Gram-negative bacteria, acute or chronic due to sensitive strains of certain gram-negative bacilli

65. Case 5 F/67 Admitted due to subarachnoid hemorrhage Desaturated on day 21, given oxygen, admitted to HDU Chest X-ray showed consolidation of right middle and lower lobe Bronchoalveolar lavage grew heavy Acinetobacter baumannii Question Appropriate known pathogen therapy?

66. Acinetobacter baumannii Common cause of nosocomial infection especially in ICU setting Drug of choice Ampicillin/sulbactam or cefoperazone/sulbactam (sulbactam highly active vs. Acinetobacter) or fluoroquinolone (ciprofloxacin, levofloxacin) Gentamicin added to prevent resistance and for synergy Imipenem, meropenem can be used

67. Case 5 Patient was given Unasyn + gentamicin for her hospital acquired pneumonia Question Any treatment options for pan-resistant strains?

68. Acinetobacter baumannii Acinetobacter strains are often resistant to antimicrobial agents Other agents with in vitro activity vs. Acinetobacter baumannii Minocycline / doxycycline Tigecycline Colistin

69. Case 6 M/40 y/o, good past health Referred by GP Presented with fever, chills and night sweats; cough initially nonproductive but became productive over past 2 months Did not recognize weight loss A sputum smear revealed acid-fast bacilli, further culture and sensitivity results pending Diagnosis: Pulmonary TB Question What is the drug(s) of choice in tuberculosis?

70. Mycobacterium tuberculosis Acid-fast bacilli, replicates very slowly (once every 24 hours vs. 20-40 mins in other organisms) Contagious and spreads through the air Disease of poverty; affecting mostly young adults in their most productive years Leading killer among HIV-infected people with weakened immune systems 8.8 million new TB cases in 2005, and 1.6 million people died from TB worldwide A curable disease with appropriate treatment

71. Mycobacterium tuberculosis Requires combination therapy The usual course of drug treatment for pulmonary TB lasts 6 months: 4 drugs in the first 2 months: isoniazid, rifampin, pyrazinamide, ethambutol/streptomycin 2 drugs in the subsequent 4 months: isoniazid, rifampin Can be given daily or three times a week Given under DOT (directly observed treatment) by healthcare staff

72. Case 6 Patient was started on isoniazid, rifampin, pyrazinamide and ethambutol Culture of sputum grew Mycobacterium tuberculosis Resistant to isoniazid and rifampin Question Is this a case of multidrug resistant TB? What agents are available?

73. Multidrug Resistant TB MDR-TB (Multidrug Resistant TB ) Resistant to isoniazid and rifampin Isoniazid and rifampin are “backbone” in first-line TB treatment Isoniazid exhibits very low MIC vs. the organism Rifampin allows short-course treatment (6-9 months) Treatment generally extends to at least 18 months without rifampin Resistance to rifampin is frequently associated with resistance to isoniazid

74. Multidrug Resistant TB

75. Multidrug Resistant TB Management Microbiologist consultation! Check susceptibility to other agents!

76. Multidrug Resistant TB

77. Tuberculosis Modify treatment plan according to Weight Hepatic function Hepatotoxic: isoniazid, rifampin Renal function Nephrotoxic: aminoglycosides Dose adjustment: fluoroquinolones (except moxifloxacin) Pregnancy: Isoniazid, rifampin, ethambutol theoretically relatively safe, insufficient safety data for pyrazinamide Penetration (e.g. in TB meningitis) Drug interactions (e.g. with anti-HIV drugs) Duration May require longer treatment in specific drug combinations, extensive diseases / extrapulmonary diseases

78. Case 6 Patient was alarmed that the organism was resistant to isoniazid and rifampin (i.e. MDR-TB) He heard of the term XDR-TB from newspaper some months ago and was very worried Question Difference(s) between MDR-TB and XDR-TB?

79. Extensive Drug Resistant TB MDR-TB (Multidrug Resistant TB) Resistant to isoniazid and rifampin XDR-TB (Extensive Drug Resistant TB) In addition to resistance vs. isoniazid and rifampin, Resistant to any fluoroquinolones, and At least one of three injectable second-line drugs (capreomycin, kanamycin and amikacin) Revised definition agreed by the WHO Global Task Force on XDR-TB in October 2006

80. Extensive Drug Resistant TB Situation worldwide XDR-TB found in USA: 4% of MDR-TB Latvia: 19% of MDR-TB S. Korea: 15% of MDR-TB May 2007: Italy reports first cases of TB resistant to all anti-TB drugs 2 cases R to all drugs and 11 XDR from 2888 culture-confirmed TB cases

81. Extensive Drug Resistant TB The facts Grave public health threat especially in populations with high HIV rates Occurs as a result of poorly-managed TB control programs If identified early, can be treated and cured in some cases under proper TB control conditions, based on the experiences in a few successful programs where HIV prevalence was low Underlines the need for investment in the development of new TB diagnostics, treatments and vaccines XDR-TB strains have been found in all regions of the world, although still thought to be uncommon Infection control measures must be strengthened everywhere, and especially where HIV prevalence is high, to protect the vulnerable and those at risk of XDR-TB

82. Extensive Drug Resistant TB

83. Extensive Drug Resistant TB

84. Reducing bacterial resistance IMPACT ( I nterhospital M ulti-disciplinary P rogramme on A ntimicrobial C hemo T herapy) Available for download at: HKU Centre of Infection http://www.hku.hk/hkucoi/impact.pdf DH Centre for Health Protection http://www.chp.gov.hk/files/pdf/reducing_bacterial_resistance_with_impact.pdf HA intranet http://ha.home/ho/ps/impact.pdf Most updated: third version 2005 (version 3.0)

85. IMPACT guideline Contents of IMPACT guideline Local antibiotic resistance Guidelines for selected antimicrobial use, e.g. Vancomycin Ceftazidime Imipenem/meropenem/ertapenem Once daily aminoglycosides Selected antifungal agents

86. IMPACT guideline Contents of IMPACT guideline Recommendations for empirical therapy of common infections Guidelines for known pathogen therapy Guidelines for surgical prophylaxis Cost and recommended dosage of commonly used antimicrobial agents

87. Antibiotic Stewardship Program Optimal selection, dosage, and duration of antimicrobial treatment that Results in the best clinical outcome for the treatment or prevention of infection With minimal toxicity to the patient and With minimal impact on subsequent resistance

88. Antibiotic Stewardship Program Involves Prescribing antimicrobial therapy only when it is beneficial to the patient Targeting therapy to the desired pathogens Using the appropriate drug, dose, and duration

89. Antibiotic Stewardship Program Should not be viewed simply as reduced use or a strategy for cost containment A strategy to enhance patient safety by Minimizing exposure to drugs Performing dose adjustments Reducing redundant therapy Targeting therapy to the likely pathogens

90. ASP in Hospital Authority Annual plan target of year 2005/06 Objectives Control the emergence and spread of antibiotic resistance Optimize selection and use of antibiotics Cost containment

91. ASP in Hospital Authority Multidisciplinary, programmatic, prospective, interventional approach to optimizing the use of antimicrobial agents The multidisciplinary team typically includes Clinical microbiologists Infectious diseases specialists Clinical pharmacists Infection control practitioners

92. ASP in Hospital Authority Overall strategies Build an antibiotic usage database in terms of usage density i.e. DDD/1000 patient-days (recommend consistent DDD definition throughout all HA units to maximize data utility) Develop a HA-wide an antibiotic resistance database of selected organisms Formation of multidisciplinary Antimicrobial Stewardship Teams (AST) in each hospital/cluster Audit use of antimicrobials based on established guidelines, e.g. IMPACT guideline Education and consensus-building Outcome measurement and user feedback

93. ASP in Hospital Authority Procedures for Antibiotic Stewardship Program using the AOF + ICF model: Obtain consensus with targeted specialties for the introduction of an Antibiotic Order Form (AOF) to monitor antibiotic usage Targeted antibiotics Big guns antibiotics IV-PO switch

94. ASP in Hospital Authority Logistics Daily review all AOFs and follow up targeted cases by assigned personnel Provide immediate concurrent feedback on prescribing to prescribers based on guidelines Monitor feedback acceptance Provide education and liaison based on guideline (e.g. educational note or face-to-face intervention) Collate and analyze data, with user feedback of the findings via educational activities

95. ASP in Hospital Authority Big gun audit Tienam, Meropenem Ceftazidime, Cefepime Tazocin, Sulperazon Vancomycin and Teicoplanin IV to oral switch Ciprofloxacin, levofloxacin, Clarithromycin, azithromycin Amoxicillin/clavulanate (Augmentin®) and fluconazole

96. Big gun audit Big gun audit Targets 2 types of antibiotics Broad-spectrum antibiotics Tienam, Meropenem, Ceftazidime, Cefepime, Tazocin, Sulperazon All these agents have good Gram-negative as well as Pseudomonas coverage Anti Gram-positive antibiotics Vancomycin and teicoplanin Active vs. methicillin-resistant Staphylococcus aureus To be used as second-line agents

97. Big gun audit Big gun audit Data collection form completed and faxed with MAR on first order of big gun Encourage physicians to prescribe big guns only when clinically indicated

98. Big gun audit

99. Big gun audit

100. IV-PO switch IV-PO switch IV antimicrobials are always required in serious infections or initial stages of infection to ensure tissue levels PO antimicrobials are useful to complete a full course of antimicrobial therapy Convenience in out-patient setting Cost effectiveness (cost of drugs + hospitalization) Decreased risk of IV-catheter related problems Except those infections of which PO antibiotics are unreliable / inappropriate

101. IV-PO switch IV-PO switch Targets IV antibiotics which Have their oral counterparts (ease of switch) Exhibit good oral bioavailability Examples Penicillins Cefuroxime Macrolides Quinolones Fluconazole

102. IV-PO switch IV-PO switch IV antimicrobials are indicated in Meningitis Intracranial abscess Infective endocarditis Mediastinitis Severe infections during chemotherapy-related neutropenia Inadequately drained abscess and empyema Severe soft tissue infections S. aureus or P. aeruginosa bacteremia

103. IV-PO switch IV-PO switch Criteria (as per IMPACT) 1. No indication for IV therapy 2. Patient is afebrile for ≥ 8 hours 3. WBC count is normalizing Falling towards or < 10 x 10 9 /L 4. Signs and symptoms related to infection are improving 5. Patient is not neutropenic Neutrophil count > 2 x 10 9 /L

104. IV-PO switch IV-PO switch Criteria (as per IMPACT) 6. Able to take drugs by mouth (non-NPO) 7. No continuous nasogastric suctioning 8. No severe nausea or vomiting, diarrhea, gastrointestinal obstruction, motility disorder 9. No malabsorption syndrome E.g. small bowel syndrome due to resection 10. No pancreatitis or active gastrointestinal bleeding or other conditions that contraindicated to the use of oral medications

105. IV-PO switch IV-PO switch Points to note Prescribe dose based on creatinine clearance when antimicrobials require renal dosage adjustment Augmentin®, Unasyn®, clarithromycin, ciprofloxacin, levofloxacin Drug interactions Oral ciprofloxacin and levofloxacin with antacid, sucralfate, didanosine, dairy products and enteral feeds

106. Useful guides to antimicrobial therapy Sanford Guide Covers a broad range of infectious diseases IMPACT With commonly prescribed empirical therapy and useful local resistance information Local antibiogram Bacterial resistance specific to an institution or a cluster of institutions

107. Conclusion New antibiotics intended to treat complicated diseases are under investigation Need to protect our antibiotic arsenal Justified use of antimicrobials not only treats infections, but also improves patient outcomes and reduces the risk of development of bacterial resistance Adherence to clinical guidelines, antimicrobial stewardship program and education helps to promote appropriate antimicrobial use

108. Conclusion Last but not least… Infection control is of utmost importance in reducing risk of infection, use of antibiotics and hence emergence of bacterial resistance Hand hygiene Appropriate isolation / contact restriction Prompt reporting of certain infectious diseases (e.g. MRSA infections) Many more!

109. End Questions and Answers