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  • Always think about TOCC in Febrile ± Influenza-like illness patients – T ravel History – recent 7 days to farms in endemic area – O ccupation – Lab worker or wild birds, poultry related – C ontact – human case and wild bird, poultry – C lustering – clustering of persons with fever and pneumonia
  • Respiratory fluoroquinolone (levofloxacin, moxifloxacin) covers both the 3 typical and 3 atypical organisms, but resistance to S pneumoniae may develop quickly, not first line therapy for estabilshed S pneumoniae infection
  • ICU setting Timentin and ceftazidime are active vs. Gram-negatives and Pseudomonas, but are less active vs. Streptococcus pneumoniae
  • Respiratory fluoroquinolone (levofloxacin, moxifloxacin) covers both the 3 typical and 3 atypical organisms, but resistance to S pneumoniae may develop quickly, not first line therapy for estabilshed S pneumoniae infection Bronchiectasis is destruction and widening of the large airways
  • Minimum inhibitory concentration tested for Penicillin G
  • Telithromycin has activity vs both typical and atypical organisms responsible for most cases of CAP
  • MDRSP refers to isolates resistant to 2 or more of the following antibiotics: penicillin, second-generation cephalosporins, macrolides, tetracycline, and trimethoprim/sulfamethoxazole.
  • Well dermarcated: well defined boundary
  • Cotrimoxazole-DS = cotrimoxazole double strength One septrin tab = 480mg DS = two tabs = 960mg
  • Staph bacteria are classified as VISA or VRSA based on laboratory tests. Laboratories perform tests to determine if staph bacteria are resistant to antimicrobial agents that might be used for treatment of infections. For vancomycin and other antimicrobial agents, laboratories determine how much of the agent it requires to inhibit the growth of the organism in a test tube. The result of the test is usually expressed as a minimum inhibitory concentration (MIC) or the minimum amount of antimicrobial agent that inhibits bacterial growth in the test tube. Therefore, staph bacteria are classified as VISA if the MIC for vancomycin is 4-8µg/ml, and classified as VRSA if the vancomycin MIC is > 16µg/ml. top
  • Oxazolidinedione Linezolid (Zyvox®) Streptogramins Quinupristin/dalfopristin (Synercid®) Pristinamycin (not yet A/V) Second generation glycopeptides Dalbavancin (Zeven®) Oritavancin (not yet A/V) Cyclic lipoglycopeptide Daptomycin (Cubicin®) Ketolide Telithromycin (Ketek®) Glycylcycline Tigecycline (Tygacil®) Polymixins Colistin (Colomycin®)
  • MDRSP refers to isolates resistant to 2 or more of the following antibiotics: penicillin, second-generation cephalosporins, macrolides, tetracycline, and trimethoprim/sulfamethoxazole.
  • Acute cholecystitis: distension of gallbladder, often with stones
  • Tazocin + aminoglycoside stated in IMPACT But associated resistance vs. penicillin is a problem
  • Acinetobacter Acinetobacter species are aerobic gram-negative bacteria that are widely distributed in soil and water and can occasionally be cultured from skin, mucous membranes, secretions, and the hospital environment. Acinetobacter baumannii is the species most commonly isolated. A baumannii has been isolated from blood, sputum, skin, pleural fluid, and urine, usually in device-associated infections. Acinetobacter encountered in nosocomial pneumonia often originates in the water of room humidifiers or vaporizers. In patients with acinetobacter bacteremia, intravenous catheters are almost always the source of infection. In patients with burns or with immune deficiencies, acinetobacter acts as an opportunistic pathogen and can produce sepsis. Acinetobacter strains are often resistant to antimicrobial agents, and therapy of infection can be difficult. Susceptibility testing should be done to help select the best antimicrobial drugs for therapy. Acinetobacter strains respond most commonly to gentamicin, amikacin, or tobramycin and to newer penicillins or cephalosporins.
  • If resistant to isoniazid but sensitive to rifampin Rifampin, pyrazinamide, ethambutol, fluoroquinolone Duration: 6 months If resistant to rifampin but sensitive to isoniazid Isoniazid, ethambutol, fluoroquinolone, pyrazinamide Duration: 12-18 months If resistant to isoniazid and rifampin Fluoroquinolone, pyrazinamide, ethambutol, injectable agent ± alternative agent Duration: 18-24 months If resistant to isoniazid, rifampin, (pyrazinamide/ethambutol) Fluoroquinolone, (pyrazinamide/ethambutol if active), injectable agent and 2 alternative agents Duration: 18-24 months

AUPDATE Presentation Transcript

  • 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