1、Antibiotic Update,Contents,Emerging and reemerging infectious diseases, antibiotic resistance, novel agents and their clinical uses Reducing bacterial resistance with IMPACT Antibiotic Stewardship Program (ASP),Conventional antibiotics,Penicillins Cephalosporins Carbapenems Quinolones Aminoglycoside
2、s Macrolides Tetracyclines,Nitrofurantoin, metronidazole, clindamycin, vancomycin, teicoplanin, cotrimoxazole, fusidic acid, etc Isoniazid, pyrazinamide, ethambutol, rifampin, cycloserine, etc,Penicillins,Penicillin G Still useful for a number of diseases (e.g. meningitis, syphilis) Cloxacillin For
3、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,Cephalosporins,Cefazolin, cephalexin Active vs. Gram-pos
4、itive 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,Carbapenems,Imipenem Broad spectrum, covers Gram-positive,
5、 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,Quinolones,Ciprofloxaci
6、n 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,Aminoglycosides,Active vs. some Gram-positive an
7、d 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 tuber
8、culosis,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,Tetracyclines,Drug of
9、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,Other anti
10、biotics,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),Other antibiotics,Cotrimox
11、azole 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 resista
12、nce,Good news vs. bad news,Good news A few novel antibiotics have shown promising results / are undergoing clinical studiesBad news As immunosuppressive diseases and use of immunosuppressive agents become more prevalent, opportunistic infections becomes more common, esp. by organisms rarely encounte
13、red 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,Emerging and reemerging infectious diseases Antibiotic
14、resistance Novel agents and their clinical uses,Part 1 Gram-positive superbugs,Gram-positive superbugs,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 cluster
15、ing non-remarkable Received a course of amoxicillin for urinary tract infection 10 weeks ago Diagnosis: Community-acquired pneumoniaQuestion What is the empirical treatment for CAP?,Community-acquired pneumonia (CAP),Microbiology “Typical” organisms Streptococcus pneumoniae Haemophilus influenzae Mo
16、raxella 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,Community-acqui
17、red 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 di
18、sease Add cover to Gram-negative enterics Tazocin / cefotaxime / ceftriaxone IV + macrolide Cefepime IV + macrolide,Community-acquired pneumonia (CAP),Empirical therapy Modifying factors Allergy to beta-lactams Fluoroquinolone (levofloxacin / moxifloxacin) Aspiration likely: anaerobes should be cove
19、red Augmentin / Unasyn / Tazocin already provide coverage Cephalosporins (except Sulperazon) is inactive Moxifloxacin Bronchiectasis: Pseudomonas cover essential Tazocin / Timentin / cefepime + macrolide Fluoroquinolone + aminoglycoside,Case 1,Patient was started on Augmentin + clarithromycin empiri
20、cally 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/mlQuestions Risk factors for penicillin-resistant S. pneumoniae? Appropriate management in this case?,Penici
21、llin 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,Penicillin resistant Streptococcus pneumoniae (PRSP),If sus
22、ceptible, penicillin group is the drug of choice for Streptococcus pneumoniae Check susceptibility and MIC if resistant to penicillinPenicillin 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 / ceftriax
23、one,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
24、resistant (MDRSP, resistant to any 2 of the following: penicillins, erythromycin, tetracycline, macrolides, cotrimoxazole) Vancomycin rifampin Clindamycin, levofloxacin, moxifloxacin could be tried,Penicillin resistant Streptococcus pneumoniae (PRSP),Any alternative for PRSP / MDRSP in respiratory t
25、ract infection?Newer agents Telithromycin (Ketek) Linezolid (Zyvox),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 me
26、ningitidis, 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,Linezolid (Zyvox),An oxazolidinedione Spectrum of activity and indications Vancomycin
27、-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 MS
28、SA 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,Case 2,M/56 Presented with skin redness, w
29、armth, swelling, tenderness on his right lower limb, a pocket of fluid palpated Diagnosis: cellulitis with pus formationQuestion Empirical treatment?,Skin and soft tissue infection,Cellulitis Microbiology Staphylococcus, Streptococci Streptococci more likely when cellulitis is well demarcated and th
30、ere are no pockets of pus or evidence of vein thrombosis,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
31、 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,Case 2,Skin tenderness and redness did not appear to improve despite Augmentin has been given
32、 Pus grew MRSA after 2 days R to methicillin, cephalothin, erythromycin S to clindamycin, vancomycin, gentamicin, cotrimoxazole Patient is clinically stableQuestions What is the drug of choice in MRSA infection? Can clindamycin be used in this case?,Methicillin resistant Staphylococcus aureus (MRSA)
33、,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-MRS
34、A 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),Healthcare-associated Multiresistant to Clindamycin Aminogly
35、cosides 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),Obtain culture for
36、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 i
37、nducible resistance) Abscess with fever, outpatient Cotrimoxazole-DS + rifampin or linezolid,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 Doxycycli
38、ne, minocycline Clindamycin Moxifloxacin Out-patient oral therapy available for uncomplicated CA-MRSA skin and soft tissue infection,Methicillin resistant Staphylococcus aureus (MRSA),Methicillin resistant Staphylococcus aureus (MRSA),Appropriate treatment in uncomplicated skin and soft tissue infec
39、tion Cotrimoxazole, doxycycline, minocycline or moxifloxacin Clindamycin is not reliable in this case Inducible clindamycin resistance due to erythromycin resistance,Case 2,What to do if the organism is resistant to agents listed above and vancomycin, and Infection is complicated (unstable patient,
40、extensive involvement, severe sepsis, etc)?,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 g/ml VRSA: vancomycin MIC is 16 g/ml (HA Central Commit
41、tee on Infectious Diseases) Susceptible: vancomycin MIC is 4g/ml VISA: vancomycin MIC is 8-16 g/ml VRSA: vancomycin MIC is 32 g/ml,VISA and VRSA,More likely to develop among patients with Underlying conditions (including renal failure) which predispose the patient to MRSA colonization; Indwelling me
42、dical 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,VISA and VRSA,Linezolid (Zyvox) (discussed in PRSP session) Quinupristin/dalfopristin (Synercid) Dalba
43、vancin (Zeven) Still under investigation Daptomycin (Cubicin) Tigecycline (Tygacil),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
44、or MRSA, Strep pyogenes, or Strep agalactiae Uncomplicated skin and skin structure infections caused by MSSA or Strep pyogenes,Quinupristin/dalfopristin (Synercid),Intravenous streptogramins (combination results in synergy) In vitro activity has been demonstrated against VISA and VRSA Spectrum of ac
45、tivity 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)
46、 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,Dalbavancin (Zeven),Second generation glycopeptide First generation: vancomyc
47、in, 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
48、 Van A gene,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 Pla
49、ce 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 infectio
50、ns,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),
