4 Penicillins Penicillin G Cloxacillin Ampicillin, amoxicillin Still useful for a number of diseases (e.g. meningitis, syphilis)CloxacillinFor MSSA infectionsAmpicillin, amoxicillinActive vs. Gram-positive (not MSSA), Gram-negative organismsAugmentin, UnasynBroad spectrum, covers Gram-positive, Gram-negative and anaerobesPiperacillin, Tazocin, TimentinAre active vs. Pseudomonas
5 Cephalosporins Cefazolin, cephalexin Cefuroxime, Cefaclor Active vs. Gram-positive organisms including MSSACefuroxime, CefaclorCovers some Gram-negative organismsCefotaxime, CeftriaxoneBroad spectrum, enhanced activity towards Gram-negative organismsCeftazidime, Cefepime, SulperazonAdditive Pseudomonas coverage
6 Carbapenems Imipenem Meropenem Ertapenem Broad spectrum, covers Gram-positive, Gram-negative (including ESBL-producing strains), Pseudomonas and anaerobesMeropenemLess seizure-inducing potential, can be used to treat CNS infectionsErtapenemLacks activity vs. Acinetobacter and PseudomonasHas limited activity against penicillin-resistant pneumococci
7 Quinolones Ciprofloxacin Levofloxacin Moxifloxacin Active vs. MSSA, Gram-negative and PseudomonasLevofloxacinHas activity vs. Streptococcus pneumoniae, but slightly less active towards Pseudomonas compared to ciprofloxacinMoxifloxacinHas activity vs. anaerobes but less active towards Pseudomonas
8 AminoglycosidesActive vs. some Gram-positive and Gram-negative organismsGentamicinActive vs. PseudomonasTobramycinMore active vs. Pseudomonas than gentamicinShows less activity against certain other Gram-negative bacteriaAmikacinMore stable to enzymes, used in severe infections by gentamicin-resistant organismsStreptomycinUsed for tuberculosis
9 Macrolides Erythromycin Clarithromycin Azithromycin Active vs. Gram-positive organisms, atypicalsGI side effectsClarithromycinSlightly greater activity than erythromycinAzithromycinSlightly less active than erythromycin vs. Gram-positive but enhanced activity vs. some Gram-negative organisms
10 TetracyclinesDrug of choice in infections caused by Chlamydia, Rickettsia, Brucella and Lyme diseaseValue has decreased due to increasing bacterial resistanceTetracyclineRole in Helicobacter pylori eradication (less frequently used than other antibiotics)DoxycyclineOnce dailyMinocyclineBroader spectrum
11 Other antibiotics Clindamycin Metronidazole Vancomycin, teicoplanin Vs. Gram-positive cocci and anaerobesMetronidazoleVs. anaerobesPreferred therapy in antibiotic associated diarrhoea (Clostridium difficile) than oral vancomycin, although unlicencedVancomycin, teicoplaninFor Gram-positive organisms (including MRSA)
12 Other antibiotics Cotrimoxazole Nitrofurantoin Fusidic acid, rifampin Role in uncomplicated UTI, UTI prophylaxis, acute exacerbations of chronic bronchitisPneumocystis carinii (now jiroveci) infectionsNitrofurantoinFor UTI, prophylaxis vs. UTIFusidic acid, rifampinFor penicillin-resistant staphylococciNot for monotherapy due to risk of emergence of resistance
13 Good news vs. bad news Good news Bad news A few novel antibiotics have shown promising results / are undergoing clinical studiesBad newsAs immunosuppressive diseases and use of immunosuppressive agents become more prevalent, opportunistic infections becomes more common, esp. by organisms rarely encountered previouslyDiseases: e.g. HIV, leukemiaDrugs: e.g. in solid organ transplants, bone marrow transplants, rheumatoid disordersDevelopment of bacterial resistance to antibiotics is much faster than research and development of new antibiotics
14 Part 1 Gram-positive superbugs Emerging and reemerging infectious diseases Antibiotic resistance Novel agents and their clinical usesPart 1Gram-positive superbugs
16 Case 1 F/74, DM on oral hypoglycemic drugs Presented with fever and malaise, cough with sputum, tachypnea; chest X-ray revealed bilateral infiltratesTravel history, occupation, contact and clustering non-remarkableReceived a course of amoxicillin for urinary tract infection 10 weeks agoDiagnosis: Community-acquired pneumoniaQuestionWhat is the empirical treatment for CAP?Always think about TOCC in Febrile ± Influenza-like illness patients– Travel History – recent 7 days to farms in endemic area– Occupation – Lab worker or wild birds, poultry related– Contact – human case and wild bird, poultry– Clustering – clustering of persons with fever andpneumonia
17 Community-acquired pneumonia (CAP) Microbiology“Typical” organismsStreptococcus pneumoniaeHaemophilus influenzaeMoraxella catarrhalis“Atypical” organismsChlamydia pneumoniaeMycoplasma pneumoniaeLegionella pneumophiliaEmpirical therapyBeta-lactams to cover typical organismsDoxycycline / macrolides to cover atypical organismsRespiratory fluoroquinolones (levo, moxi) for beta-lactam allergyRespiratory 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
18 Community-acquired pneumonia (CAP) Empirical therapy (as per IMPACT)CAP, out-patientAugmentin/Unasyn PO ± macrolide POAmoxicillin PO + clarithromycin / azithromycin POCAP, hospitalized in general wardAugmentin / Unasyn IV/PO ± macrolideCefotaxime / ceftriaxone IV ± macrolideCAP, hospitalized in ICU for serious diseaseAdd cover to Gram-negative entericsTazocin / cefotaxime / ceftriaxone IV + macrolideCefepime IV + macrolideICU settingTimentin and ceftazidime are active vs. Gram-negatives and Pseudomonas, but are less active vs. Streptococcus pneumoniae
19 Community-acquired pneumonia (CAP) Empirical therapyModifying factorsAllergy to beta-lactamsFluoroquinolone (levofloxacin / moxifloxacin)Aspiration likely: anaerobes should be coveredAugmentin / Unasyn / Tazocin already provide coverageCephalosporins (except Sulperazon) is inactiveMoxifloxacinBronchiectasis: Pseudomonas cover essentialTazocin / Timentin / cefepime + macrolideFluoroquinolone + aminoglycosideRespiratory 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 infectionBronchiectasis is destruction and widening of the large airways
20 Case 1 Patient was started on Augmentin + clarithromycin empirically 3 days later, fever persisted, chest X-ray showed progressive pneumoniaEndotracheal aspirate (WBC +++, few epithelial cells) grew heavy Streptococcus pneumoniae, with penicillin MIC > 4mcg/mlQuestionsRisk factors for penicillin-resistant S. pneumoniae?Appropriate management in this case?
21 Penicillin resistant Streptococcus pneumoniae (PRSP) Risk factorsAge > 65 yearsBeta-lactam therapy in past 3 monthsAlcoholismMultiple 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 pneumoniaeCheck susceptibility and MIC if resistant to penicillinPenicillin susceptible (MIC 0.1 mcg/ml)Penicillin G, amoxicillinPenicillin resistant (0.1< MIC 1.0 mcg/ml)High dose penicillin G or ampicillin, cefotaxime / ceftriaxoneMinimum inhibitory concentration tested for Penicillin G
23 Penicillin resistant Streptococcus pneumoniae (PRSP) Penicillin resistant (MIC > 2.0 mcg/ml)Vancomycin rifampinHigh dose cefotaxime tried in meningitisNon-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)Clindamycin, levofloxacin, moxifloxacin could be tried
24 Penicillin resistant Streptococcus pneumoniae (PRSP) Any alternative for PRSP / MDRSP in respiratory tract infection?Newer agentsTelithromycin (Ketek®)Linezolid (Zyvox®)
25 Telithromycin (Ketek®) A ketolide (structurally related to macrolides)Spectrum of activityGroup A, B, C and G Streptococci, Streptococcus pneumoniae (including multidrug resistant strains), MSSAListeria monocytogenes, Neisseria meningitidis, Moraxella catarrhalis, Haemophilus influenzaeLegionella, Chlamydia, MycoplasmaNo activity vs. MRSA, GRE, or any enteric gram-negative bacteriaIndicationsMild to moderate community acquired pneumoniaTelithromycin has activity vs both typical and atypical organisms responsible for most cases of CAP
26 Linezolid (Zyvox®) Spectrum of activity and indications An oxazolidinedioneSpectrum of activity and indicationsVancomycin-Resistant Enterococcus faecium infections, including cases with concurrent bacteremiaNosocomial 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 agalactiaeUncomplicated 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 MSSAMDRSP refers to isolates resistant to 2 or more of the following antibiotics: penicillin, second-generation cephalosporins, macrolides, tetracycline, and trimethoprim/sulfamethoxazole.
27 Case 2M/56Presented with skin redness, warmth, swelling, tenderness on his right lower limb, a pocket of fluid palpatedDiagnosis: cellulitis with pus formationQuestionEmpirical treatment?
28 Skin and soft tissue infection CellulitisMicrobiologyStaphylococcus, StreptococciStreptococci more likely when cellulitis is well demarcated and there are no pockets of pus or evidence of vein thrombosisWell dermarcated: well defined boundary
29 Staphylococcus aureus If susceptible, penicillinase-resistant penicillins are the drugs of choice for methicillin-susceptible Staphylococcus aureus (MSSA)Drug of choiceCloxacillin, flucloxacillinCefazolin, cephalexin (penicillin allergic but tolerate cephs)With beta-lactamase inhibitorAs two-agent combination in Augmentin, UnasynErythromycin, clindamycin (if penicillin allergic)The above antibiotics also have good activity vs. Streptococci
30 Case 2Skin tenderness and redness did not appear to improve despite Augmentin has been givenPus grew MRSA after 2 daysR to methicillin, cephalothin, erythromycinS to clindamycin, vancomycin, gentamicin, cotrimoxazolePatient is clinically stableQuestionsWhat is the drug of choice in MRSA infection?Can clindamycin be used in this case?
31 Methicillin resistant Staphylococcus aureus (MRSA) Healthcare-associatedEndemic in hospitals, old age homesRisk factorsHospitalization in previous 1 yearRecent surgeryOld age home residenceRenal dialysisExposure to invasive devicesEmployment in a healthcare instituteCommunity-associatedDo not have usual risk factors associated with HA-MRSAMore common in the following in overseas countriesChildren with chronic skin conditionPrisonersMilitary personnelAboriginalsInjection drug usersThe homelessContact sports athletes
32 Methicillin resistant Staphylococcus aureus (MRSA) Healthcare-associatedMultiresistant toClindamycinAminoglycosidesTetracyclinesFluoroquinolonesCommunity-associatedOften remains susceptible toClindamycinAminoglycosidesTetracyclinesFluoroquinolonesMore 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 37th ed)Community-associatedMild to moderate infectionsAbscess, afebrile, immunocompetent, outpatientCotrimoxazole / doxycycline / minocycline rifampinClindamycin (do not use if R to erythromycin due to inducible resistance)Abscess with fever, outpatientCotrimoxazole-DS + rifampin or linezolidCotrimoxazole-DS = cotrimoxazole double strengthOne septrin tab = 480mgDS = two tabs = 960mg
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:CotrimoxazoleDoxycycline, minocyclineClindamycinMoxifloxacinOut-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)AgentPotential advantagePrecautionsUsual adult dose (oral)CotrimoxazoleOralNot for patient with sulfa allergy / G6PD960mg bdDoxycyclineHigh skin concentrationNot for children <12 yo or pregnant women200mg once, then 100mg bdMinocyclineAs above100mg bdClindamycinInhibit toxin productionInducible resistance if erythromycin resistantmg tdsMoxifloxacinResistance may develop during therapy400mg qd
36 Methicillin resistant Staphylococcus aureus (MRSA) Appropriate treatment in uncomplicated skin and soft tissue infectionCotrimoxazole, doxycycline, minocycline or moxifloxacinClindamycin is not reliable in this caseInducible clindamycin resistance due to erythromycin resistance
37 Case 2What to do ifthe organism is resistant to agents listed above and vancomycin, andInfection is complicated (unstable patient, extensive involvement, severe sepsis, etc)?
38 VISA and VRSA VISA: vancomycin-intermediate Staph aureus VRSA: vancomycin-resistant Staph aureusClassified based on minimum inhibitory concentration (MIC)(CDC definition)VISA: vancomycin MIC is 4-8 µg/mlVRSA: vancomycin MIC is >16 µg/ml(HA Central Committee on Infectious Diseases)Susceptible: vancomycin MIC is ≤ 4µg/mlVISA: vancomycin MIC is 8-16 µg/mlVRSA: vancomycin MIC is >32 µg/mlStaph 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
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/orMRSA infection requiring treatment with vancomycin for a prolonged periodUsually isolated during vancomycin (or teicoplanin) therapy for MRSA infections which fail to respond
40 VISA and VRSA Linezolid (Zyvox®) Quinupristin/dalfopristin (Synercid®) (discussed in PRSP session)Quinupristin/dalfopristin (Synercid®)Dalbavancin (Zeven®)Still under investigationDaptomycin (Cubicin®)Tigecycline (Tygacil®)OxazolidinedioneLinezolid (Zyvox®)StreptograminsQuinupristin/dalfopristin (Synercid®)Pristinamycin (not yet A/V)Second generation glycopeptidesDalbavancin (Zeven®)Oritavancin (not yet A/V)Cyclic lipoglycopeptideDaptomycin (Cubicin®)KetolideTelithromycin (Ketek®)GlycylcyclineTigecycline (Tygacil®)PolymixinsColistin (Colomycin®)
41 Linezolid (Zyvox®) Demonstrate bacteriostatic action vs. VISA and VRSA IndicationsComplicated skin and skin structure infections, including diabetic foot infections, without concomitant osteomyelitis, caused by MSSA or MRSA, Strep pyogenes, or Strep agalactiaeUncomplicated skin and skin structure infections caused by MSSA or Strep pyogenesMDRSP refers to isolates resistant to 2 or more of the following antibiotics: penicillin, second-generation cephalosporins, macrolides, tetracycline, and trimethoprim/sulfamethoxazole.
42 Quinupristin/dalfopristin (Synercid®) Intravenous streptogramins (combination results in synergy)In vitro activity has been demonstrated against VISA and VRSASpectrum of activityVancomycin-resistant Enterococcus faeciumPenicillin-resistant Streptococcus pneumoniaeMethicillin-resistant StaphylococciVancomycin-resistant Enterococcus faecalis is relatively resistant to quinopristin/dalfopristinAnaerobes and some gram-negative pathogens (e.g., Haemophilus influenzae) have also been susceptibleIndicationsBacteremia - Vancomycin-resistant Enterococcus faecium infectionInfection of skin and/or subcutaneous tissue, Complicated, caused by Staphylococcus aureus and Streptococcus pyogenes
43 Dalbavancin (Zeven®) Second generation glycopeptide First generation: vancomycin, teicoplaninSpectrum of activityStaphylococci and Streptococci, including resistant isolatesClostridium spp., Peptostreptococcus spp., Actiniomyces spp., Corynebacterium spp. and Bacillus subtilisNo activity vs. most gram-negative bacteriaNo 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. aureusAlso, methicillin-susceptible, methicillin-resistant, and vancomycin-intermediate Coagulase negative Staphylococci strains have had favorable in vitro resultsPlace of therapy (no FDA approved indication at the moment)Currently in phase III trials for treatment of resistant gram-positive organismsPublished 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 lipoglycopeptideSpectrum of activityMSSA, MRSA, Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus dysgalactiae subsp. equisimilis, andEnterococcus faecalis (vancomycin-susceptible isolates only)IndicationsComplicated skin and skin structure infections caused by susceptible Gram-positive microorganismsStaphylococcus aureus bloodstream infections including those with right-sided infective endocarditis (methicillin-susceptible and methicillin-resistant) (native valve)
46 Tigecycline (Tygacil®) A glycylcyclineDerived from minocyclineA very broad spectrum antibioticCovers many resistant strains of Gram-positive, Gram-negative, and anaerobic organismsNote active vs. PseudomonasBoth in vitro and in vivo activities have been demonstrated against MSSA, MRSA, and VISA
47 Tigecycline (Tygacil®) IndicationsComplicated skin and skin structure infections byEscherichia coliEnterococcus faecalis (vancomycin-susceptible isolates only)Staphylococcus aureus (Methi-S or Methi-R)Streptococcus agalactiaeStreptococcus anginosus grp.Streptococcus pyogenesBacteroides fragilisComplicated intra-abdominal infections byCitrobacter freundiiEnterobacter cloacaeE. coli, K. oxytoca, K. pneumoniaeEnterococcus faecalis (Vanco-S isolates only)Staphylococcus aureus (Methi-S or Methi-R)Streptococcus anginosus groupBacteriodes fragilisClostridium perfringensPeptostreptococcus micros
48 Part 2 Gram-negative superbugs Emerging and reemerging infectious diseases Antibiotic resistance Novel agents and their clinical usesPart 2Gram-negative superbugs
50 Case 3M/59Presented with 2-day history of right upper quadrant pain, fever, jaundiceEmesis x 2 past 24 hours, dark color urineElevated LFTRadiologic finding: dilated common bile duct, no increase in gallbladder sizeDiagnosis: acute cholangitisQuestionWhat is the empirical therapy?Acute cholecystitis: distension of gallbladder, often with stones
52 Acute cholangitis/cholecystitis Adequate drainage is essentialEmpirical treatment complementary to drainageAugmentin/Unasyn ± aminoglycosideTimentinCefuroxime + metronidazoleCiprofloxacin (if beta-lactam allergic)
53 Case 3Biliary drainage performed with cefuroxime + metronidazole pre- and post-operationBecame septic (with high fever, tachycardia, WBC > 12 x 109/L) 2 days post-opBlood culture grew E. coli (ESBL-producing), moderately sensitive to Augmentin, sensitive to Sulperazon and imipenemQuestionWhat is the appropriate treatment?Can Augmentin or Sulperazon be used?
54 EnterobacteriaceaeSusceptible strains of E. coli and Klebsiella are sensitive toAugmentin/UnasynCefuroxime (if resistant to above)Other anti gram-negative penicillins/cephs also workFluoroquinolones (if allergic to beta-lactams)
55 ESBL-producing Enterobacteriaceae Extended-spectrum beta-lactamasesAny bacterial enzymes that are capable of inactivating third generation cephalosporinsGenerally regarded as resistant to penicillins and cephalosporinsDrug of choiceUrinary tract infectionCotrimoxazole, Augmentin, nitrofurantoin, levofloxacin / ciprofloxainOther serious infectionsCarbapenems: imipenem, meropenem, ertapenem (reliable activity vs. ESBL-producing Enterobacteriaceae)Fluoroquinolone + aminoglycosideTazocin + aminoglycoside stated in IMPACTBut associated resistance vs. penicillin is a problem
56 Case 3 Augmentin and Sulperazon are not appropriate Appropriate agent Patient is clinically septic (likely due to the ESBL-producing strain of E. coli)The strain is only apparently susceptible to the above agentsAppropriate agentErtapenem (no activity vs. Pseudomonas)Imipenem (when activity vs. Pseudomonas required)
57 Case 4 M/33 Victim of road traffic accident Experienced severe burns during accidentEarly excision and repair performed; silver sulfadiazine cream topicallyHigh fever on day 5, blood culture grew Pseudomonas aeruginosa on day 7QuestionAppropriate known pathogen therapy?
58 Pseudomonas aeruginosa Gram-negative bacilliFrequently present in small numbers in the normal intestinal flora and on the skin of humans and is the major pathogenCauses diseases in patients with abnormal host defenses, e.g.When mucous membranes and skin are disruptedWhen intravenous or urinary catheters are usedWhen neutropenia is present (as in chemotherapy)Intrinsically resistant to many antibiotics
59 Pseudomonas aeruginosa Drug of choiceAntipseudomonal penicillins/cephalosporinsPiperacillin, piperacillin/tazobactam (Tazocin), ticarcillin/clavulanate (Timentin)Ceftazidime, cefoperazone, cefepimeCarbapenemsImipenem, meropenem (NOT ertapenem)AminoglycosidesGentamicin, tobramycin, amikacinFluoroquinolonesCiprofloxacin, levofloxacin (less activity than cipro)Often a two-drug combination is employed except in uncomplicated UTI
60 Case 4Tazocin (Piperacillin/tazobactam) plus gentamicin were prescribedMicrobiologist suggested using piperacillin plus gentamicin is sufficient for this patientQuestionWhat is the difference in activities (and hence uses) between Tazocin and piperacillin?
61 Piperacillin vs. Tazocin Tazobactam in Tazocin®Tazobactam is a beta-lactamase inhibitorRenders the combination of Tazocin® more active againstGram positive: MSSAGram negative: Haemophilus influenzae and othersAnaerobe: 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 equivalentAt common usual dose (HA Corp drug price as of May 2007)Piperacillin 4g/vial: $56Tazocin® 4.5g/vial: $108
63 Multidrug resistant Gram-negative organisms Any treatment options forESBL-producing Enterobacteriaceae, orPseudomonas aeruginosa,that are pan-resistant?
64 Colistin (Colomycin®) Indeed an old, toxic drug!a.k.a. Polymyxin E, colistimethate sodiumNow being used with increasing frequency due to necessity (multidrug resistant Gram-negatives)Risk of neurotoxicity and nephrotoxicitySpectrum of activity (check susceptibility!)Pseudomonas aeruginosa, Acinetobacter spp.E. coli and Klebsiella (incl. ESBL-producing strains), Enterobacter spp.Citrobacter spp, Hemophilus spp.IndicationsDisease 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 HDUChest X-ray showed consolidation of right middle and lower lobeBronchoalveolar lavage grew heavy Acinetobacter baumanniiQuestionAppropriate known pathogen therapy?
66 Acinetobacter baumannii Common cause of nosocomial infection especially in ICU settingDrug of choiceAmpicillin/sulbactam or cefoperazone/sulbactam (sulbactam highly active vs. Acinetobacter) or fluoroquinolone (ciprofloxacin, levofloxacin)Gentamicin added to prevent resistance and for synergyImipenem, meropenem can be usedAcinetobacterAcinetobacter 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.
67 Case 5Patient was given Unasyn + gentamicin for her hospital acquired pneumoniaQuestionAny treatment options for pan-resistant strains?
68 Acinetobacter baumannii Acinetobacter strains are often resistant to antimicrobial agentsOther agents with in vitro activity vs. Acinetobacter baumanniiMinocycline / doxycyclineTigecyclineColistin
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 monthsDid not recognize weight lossA sputum smear revealed acid-fast bacilli, further culture and sensitivity results pendingDiagnosis: Pulmonary TBQuestionWhat is the drug(s) of choice in tuberculosis?
70 Mycobacterium tuberculosis Acid-fast bacilli, replicates very slowly (once every 24 hours vs mins in other organisms)Contagious and spreads through the airDisease of poverty; affecting mostly young adults in their most productive yearsLeading killer among HIV-infected people with weakened immune systems8.8 million new TB cases in 2005, and 1.6 million people died from TB worldwideA curable disease with appropriate treatment
71 Mycobacterium tuberculosis Requires combination therapyThe usual course of drug treatment for pulmonary TB lasts 6 months:4 drugs in the first 2 months: isoniazid, rifampin, pyrazinamide, ethambutol/streptomycin2 drugs in the subsequent 4 months: isoniazid, rifampinCan be given daily or three times a weekGiven under DOT (directly observed treatment) by healthcare staff
72 Case 6Patient was started on isoniazid, rifampin, pyrazinamide and ethambutolCulture of sputum grew Mycobacterium tuberculosisResistant to isoniazid and rifampinQuestionIs this a case of multidrug resistant TB?What agents are available?
73 Multidrug Resistant TB MDR-TB (Multidrug Resistant TB )Resistant to isoniazid and rifampinIsoniazid and rifampin are “backbone” in first-line TB treatmentIsoniazid exhibits very low MIC vs. the organismRifampin allows short-course treatment (6-9 months)Treatment generally extends to at least 18 months without rifampinResistance to rifampin is frequently associated with resistance to isoniazid
75 Multidrug Resistant TB ManagementMicrobiologist consultation!Check susceptibility to other agents!If resistant to isoniazid but sensitive to rifampinRifampin, pyrazinamide, ethambutol, fluoroquinoloneDuration: 6 monthsIf resistant to rifampin but sensitive to isoniazidIsoniazid, ethambutol, fluoroquinolone, pyrazinamideDuration: monthsIf resistant to isoniazid and rifampinFluoroquinolone, pyrazinamide, ethambutol, injectable agent ± alternative agentDuration: monthsIf resistant to isoniazid, rifampin, (pyrazinamide/ethambutol)Fluoroquinolone, (pyrazinamide/ethambutol if active), injectable agent and 2 alternative agents
77 Tuberculosis Modify treatment plan according to Weight Hepatic functionHepatotoxic: isoniazid, rifampinRenal functionNephrotoxic: aminoglycosidesDose adjustment: fluoroquinolones (except moxifloxacin)Pregnancy: Isoniazid, rifampin, ethambutol theoretically relatively safe, insufficient safety data for pyrazinamidePenetration (e.g. in TB meningitis)Drug interactions (e.g. with anti-HIV drugs)DurationMay require longer treatment in specific drug combinations, extensive diseases / extrapulmonary diseases
78 Case 6Patient 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 worriedQuestionDifference(s) between MDR-TB and XDR-TB?
79 Extensive Drug Resistant TB MDR-TB (Multidrug Resistant TB)Resistant to isoniazid and rifampinXDR-TB (Extensive Drug Resistant TB)In addition to resistance vs. isoniazid and rifampin,Resistant to any fluoroquinolones, andAt 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 worldwideXDR-TB found inUSA: 4% of MDR-TBLatvia: 19% of MDR-TBS. Korea: 15% of MDR-TBMay 2007: Italy reports first cases of TB resistant to all anti-TB drugs2 cases R to all drugs and 11 XDR from 2888 culture-confirmed TB cases
81 Extensive Drug Resistant TB The factsGrave public health threat especially in populations with high HIV ratesOccurs as a result of poorly-managed TB control programsIf 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 lowUnderlines the need for investment in the development of new TB diagnostics, treatments and vaccinesXDR-TB strains have been found in all regions of the world, although still thought to be uncommonInfection control measures must be strengthened everywhere, and especially where HIV prevalence is high, to protect the vulnerable and those at risk of XDR-TB
84 Reducing bacterial resistance IMPACT (Interhospital Multi-disciplinary Programme on Antimicrobial ChemoTherapy)Available for download at:HKU Centre of InfectionDH Centre for Health ProtectionHA intranetMost updated: third version 2005 (version 3.0)
85 IMPACT guideline Contents of IMPACT guideline Local antibiotic resistanceGuidelines for selected antimicrobial use, e.g.VancomycinCeftazidimeImipenem/meropenem/ertapenemOnce daily aminoglycosidesSelected antifungal agents
86 IMPACT guideline Contents of IMPACT guideline Recommendations for empirical therapy of common infectionsGuidelines for known pathogen therapyGuidelines for surgical prophylaxisCost and recommended dosage of commonly used antimicrobial agents
87 Antibiotic Stewardship Program Optimal selection, dosage, and duration of antimicrobial treatment thatResults in the best clinical outcome for the treatment or prevention of infectionWith minimal toxicity to the patient andWith minimal impact on subsequent resistance
88 Antibiotic Stewardship Program InvolvesPrescribing antimicrobial therapy only when it is beneficial to the patientTargeting therapy to the desired pathogensUsing the appropriate drug, dose, and duration
89 Antibiotic Stewardship Program Should not be viewed simply as reduced use or a strategy for cost containmentA strategy to enhance patient safety byMinimizing exposure to drugsPerforming dose adjustmentsReducing redundant therapyTargeting therapy to the likely pathogens
90 ASP in Hospital Authority Annual plan target of year 2005/06ObjectivesControl the emergence and spread of antibiotic resistanceOptimize selection and use of antibioticsCost containment
91 ASP in Hospital Authority Multidisciplinary, programmatic, prospective, interventional approach to optimizing the use of antimicrobial agentsThe multidisciplinary team typically includesClinical microbiologistsInfectious diseases specialistsClinical pharmacistsInfection control practitioners
92 ASP in Hospital Authority Overall strategiesBuild 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 organismsFormation of multidisciplinary Antimicrobial Stewardship Teams (AST) in each hospital/clusterAudit use of antimicrobials based on established guidelines, e.g. IMPACT guidelineEducation and consensus-buildingOutcome 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 usageTargeted antibioticsBig guns antibioticsIV-PO switch
94 ASP in Hospital Authority LogisticsDaily review all AOFs and follow up targeted cases by assigned personnelProvide immediate concurrent feedback on prescribing to prescribers based on guidelinesMonitor feedback acceptanceProvide 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 auditTienam, MeropenemCeftazidime, CefepimeTazocin, SulperazonVancomycin and TeicoplaninIV to oral switchCiprofloxacin, levofloxacin,Clarithromycin, azithromycinAmoxicillin/clavulanate (Augmentin®) and fluconazole
96 Big gun audit Big gun audit Targets 2 types of antibiotics Broad-spectrum antibioticsTienam, Meropenem, Ceftazidime, Cefepime, Tazocin, SulperazonAll these agents have good Gram-negative as well as Pseudomonas coverageAnti Gram-positive antibioticsVancomycin and teicoplaninActive vs. methicillin-resistant Staphylococcus aureusTo 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 gunEncourage physicians to prescribe big guns only when clinically indicated
100 IV-PO switch IV-PO switch IV antimicrobials are always required in serious infections or initial stages of infection to ensure tissue levelsPO antimicrobials are useful to complete a full course of antimicrobial therapyConvenience in out-patient settingCost effectiveness (cost of drugs + hospitalization)Decreased risk of IV-catheter related problemsExcept those infections of which PO antibiotics are unreliable / inappropriate
101 IV-PO switch IV-PO switch Targets IV antibiotics which Examples Have their oral counterparts (ease of switch)Exhibit good oral bioavailabilityExamplesPenicillinsCefuroximeMacrolidesQuinolonesFluconazole
102 IV-PO switch IV-PO switch IV antimicrobials are indicated in MeningitisIntracranial abscessInfective endocarditisMediastinitisSevere infections during chemotherapy-related neutropeniaInadequately drained abscess and empyemaSevere soft tissue infectionsS. aureus or P. aeruginosa bacteremia
103 IV-PO switch IV-PO switch Criteria (as per IMPACT) 1. No indication for IV therapy2. Patient is afebrile for ≥ 8 hours3. WBC count is normalizingFalling towards or < 10 x 109/L4. Signs and symptoms related to infection are improving5. Patient is not neutropenicNeutrophil count > 2 x 109/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 suctioning8. No severe nausea or vomiting, diarrhea, gastrointestinal obstruction, motility disorder9. No malabsorption syndromeE.g. small bowel syndrome due to resection10. 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 adjustmentAugmentin®, Unasyn®, clarithromycin, ciprofloxacin, levofloxacinDrug interactionsOral ciprofloxacin and levofloxacin with antacid, sucralfate, didanosine, dairy products and enteral feeds
106 Useful guides to antimicrobial therapy Sanford GuideCovers a broad range of infectious diseasesIMPACTWith commonly prescribed empirical therapy and useful local resistance informationLocal antibiogramBacterial resistance specific to an institution or a cluster of institutions
107 ConclusionNew antibiotics intended to treat complicated diseases are under investigationNeed to protect our antibiotic arsenalJustified use of antimicrobials not only treats infections, but also improves patient outcomes and reduces the risk of development of bacterial resistanceAdherence 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 resistanceHand hygieneAppropriate isolation / contact restrictionPrompt reporting of certain infectious diseases (e.g. MRSA infections)Many more!