Antimicrobial Agents 101 - SWACM

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Antimicrobial Agents 101 - SWACM

Antimicrobial Agents 101SWACM 2011Christopher Doern, Ph.D., D(ABMM)


β -Lactams• Penicillins• Cephalosporins• Carbapenems• Monobactamsβ -LactamaseInhibitors• Clavulanate– Amox/Clav– Ticar/Clav• Sulbactam– Amp/Sulb• Tazobactam– Pip/TazoBack to Basics:Cell Wall Acting Antibiotics• Bactericidal• Inhibit cell wallsynthesis by blockingtranspeptidase(Penicillin bindingprotein or PBP)activity.• Weak antibacterialactivity• Potent inhibitors ofsome β-lactamases


Beta-lactam Videohttp://www.youtube.com/watch_popup?v=qBdYnRhdWcQ&vq=medium


Beta-Lactam Spectrum of ActivityActive*• Aerobic and anaerobic Grampositive cocci and bacilli• Aerobic and anaerobic Gramnegative bacilli• Beta-Lactamase inhibitors used toinhibit beta-lactamases producedby anaerobes• Other organisms– Pasteurella– Streptobacillus– Treponema pallidum– ErysypelothrixInactive• Carbapenemase producing Gramnegative bacilli• Ampicillin resistant Enterococci• Mycoplasma• Stenotrophomonas maltophilia• MRSA*In many cases susceptibility testing necessary to confirm activity of specific classof beta-lactam against individual isolates.


Common Clinical Indications for Beta-LactamsPenicillin or Ampicillin– Severe Enterococcal infection(plus gentamicin for synergy)– GAS and GBS– Actinomyces– SyphillisBeta-lactam + inhibitor– Bite wounds• Infections expected to includeanaerobes– Uncomplicated UTI– GAS pharyngitis– Otitis media– Pip/Tazo• P. aeruginosaKucers’: The Use of Antibiotics, 6 th EditionCefazolin and Cefalothin* (1 st gen cephs)– MSSA infection*Itself rarely used but predicts susceptibility to oral1 st gen cephsCefotaxime and Ceftriaxone– Empiric treatment for meningitis• Ampicillin added to those


Back to Basics:Other Cell Wall Acting AntibioticsGlycopeptides• Vancomycin• TeicoplaninLipopeptides• DaptomycinPolymyxins• Colistin• Inhibits assembly ofpeptidoglycan precursors(murein)– Slowly bactericidal• Binds to cell membraneand disrupts bacterial cellmembrane potential– Rapidly bactericidal• Penetrate and disrupt cellmembranes– Rapidly bactericidal


Spectrum of ActivityActive*Glycopeptides and Lipopeptides• Gram positive cocci and bacilliInactiveGlycopeptides and Lipopeptides• Gram negativesPolymyxins• Gram negativePolymyxins• Gram positives• Anaerobes• Burkholderia• Proteus• Serratia• Providencia*In many cases susceptibility testing necessary to confirm activity of specific classof beta-lactam against individual isolates.


Common Clinical Indications for UseVancomycin– Empiric coverage for Gram positiveinfection– MRSA– Recurrent C. difficile infectionDaptomycin– VRE– MRSA – non-respiratoryColistin– Hospital acquired ventilator associatedpneumonia• MDR Acinetobacter• MDR Gram negatives– Can be nebulized for respiratoryinfectionsMedical Letter, Inc. June 2010


Back to Basics:Protein Synthesis InhibitorsOxazolidinones• LinezolidTetracyclines andChloramphenicol• Doxy-, Mino-, Tetra-,Tigecycline• Chloramphenicolwww.accessmedicine.nethttp://pharmaxchange.info/press/wp-content/uploads/2011/06/oxazolidinone-115x115.png


Back to Basics:Protein Synthesis InhibitorsMLSb Antibiotics• Macrolides– Erythromycin,Clarithromycin andAzithromycin• Lincosamides– Clindamycin• Streptograminswww.accessmedicine.net– Synercid• Bind 50S subunit andinhibit peptide chainelongation• Bind 50S and inhibit bothaddition of peptides andchain elongation


Macrolide Videohttp://www.youtube.com/watch_popup?v=oC21vLFtsjo&vq=medium


Spectrum of ActivityLinezolid• Gram positives• Nocardia• MycobacteriaActive*Tetracyclines and Chloramphenicol• Aerobic and anaerobic Grampositives• Aerobic and anaerobic Gramnegatives• Spirochetes• Rickettsiae, chlamydiae,mycoplasmas and protozoansInactiveLinezolid• Gram negatives• Mycoplasmas and ureaplasmas*In many cases susceptibility testing necessary to confirm activity of specific classof beta-lactam against individual isolates.


Spectrum of ActivityMacrolidesActive*• Aerobic and anaerobic Grampositives and Gram negatives• Treponemes, mycoplasmas,Chlamydia and rickettsiaeLincosamides• Aerobic and anaerobic Grampositives and Gram negativesStreptogramins• Aerobic and anaerobic Grampositives• Some Gram negativesInactiveLincosamides• EnterobacteriaceaeStreptogramins• Enterococcus faecalis• Enterobacteriaceae• Pseudomonas aeruginosa• Acinetobacter*In many cases susceptibility testing necessary to confirm activity of specific classof beta-lactam against individual isolates.


Common Clinical Indications for UseAzithromycin– Legionella– Chlamydia– Acute otitis media– Acute exacerbations of chronicbronchitis– CAP in low MDR risk patients– Pertusiss– Shigella in children– Immunomodulating agent in CFLinezolid– MRSA• Skin and soft-tissue infection• Pneumonia– VREClindamycin (not exhaustive)– S. aureus infections (MRSA and MSSA)– Skin and connective tissue infections• Bites, acne, cellulitis, necrotizing fasciitis…to name afew– Bone and joint infections– Bacterial pneumonia– Abscesses• Skin, head and neck, retro and parapharyngeal– Toxin producing infections caused by GrampositivesDoxycycline– Tick-borne disease• Ehrlichia, Lyme disease, Typhus, RMSF– Chlamydia– Pelvic inflammatory disease– Bartonella– Prophylaxis for agents of bioterrorismKucers’: The Use of Antibiotics, 6 th EditionMedical Letter, Inc. June 2010


Back to Basics:Protein Synthesis InhibitorsAminoglycosides• Gentamicin, Amikacin,Tobramycin,Spectinomycin andmany more…• Interfere with proofreadingmechanismresulting in prematuretermination• Interfere with proteinsynthesis by blockingribosomal tranlocation• Can disrupt integrity ofcell membrane• Some bind to 50S andother 30S subunit


Aminoglycoside Spectrum of ActivityActive*• Aerobic Gram positives and Gramnegatives• MycobacteriaInactive• Anaerobes• MRSA• S. pneumoniae• Stenotrophomonas maltophilia• Burkholderia cepacia*In many cases susceptibility testing necessary to confirm activity of specific classof beta-lactam against individual isolates.


Common Clinical Indications for UseAminoglycosides– Synergy with beta-lactam• Viridans group streptococci(Gentamicin)• Listeria (Gentamicin)• Pseudomonas aeruginosa (Pip/Tazo)• Enterococcus spp. (high level)– Tularemia, plague and Brucella– Complicated UTI– Serious Gram negative infectionsKucers’: The Use of Antibiotics, 6 th EditionMedical Letter, Inc. June 2010


Quinolone Videohttp://www.youtube.com/watch_popup?v=IkKZ_gxAOXI&vq=medium


Quinolone Spectrum of ActivityActive*Inactive• Aerobic Gram negatives andGram positives• Anaerobic Gram negatives andGram positives• Mycobacteria• Mycoplasma, Chlamydia andTreponema*In many cases susceptibility testing necessary to confirm activity of specific classof beta-lactam against individual isolates.


Back to Basics:RNA Synthesis InhibitorsRifamycins– Rifampicin (rifampin),rifabutin, rifapentine• Interferes with DNAdependentRNApolymerase to inhibitRNA synthesisSassetti and Rubin. 2007. Nat. Med.


Rifamycin Spectrum of ActivityActive*Inactive• Mycobacterium tuberculosis• Non-tuberculous mycobacteria• Gram positive cocci• Gram negative bacilli• Some anaerobes• Neisseria meningitidis(oropharyngeal clearance)• Other organisms– Chlamydia– Bartonella– Legionella– H. pylori– Ehrlichia– Brucella*In many cases susceptibility testing necessary to confirm activity of specific classof beta-lactam against individual isolates.


Common Clinical Indications for UseRifampin– Haemophilus influenzae type B andN. meningitis contact prophylaxis– TB , MAI and other mycobacteria– Combination therapy• Serious staphylococcal infection• Brucella infections– Bartonella infection– Coxiella infectionMedical Letter, Inc. June 2010


Recommendations for Top 6 Infections1. Skin and soft tissueUncomplicated: MRSA, MSSA, Group A StreptococcusRecommendation:MRSA - Drainage alone, bactrim, doxy, clinda or linezolidNon-MRSA – 1 st gen ceph, if hospitalized nafcillin or cefazolin, clinda or vanc.Complicated: Above plus Gram negative bacilli (E. coli and P. aeruginosa)Recommendation:Vanc, dapto and linezolidIf polymicrobic w/out MRSA – amp/sulb, pip/tazo, carbapenem (not erta)If GAS or Clostridium likely – clinda plus penicillin


Recommendations for Top 6 Infections2. Bone and JointAcute Osteomyelitis: Common – S. aureus, Group A StreptococcusRare – Salmonella, E. coli, PARecommendation: MRSA – Empiric = vanc, Confirmed = Dapto, Vanc or LzdGC = CeftriaxoneStreptococci = Pen or CeftriaxoneChronic Osteomyelitis:Recommendation :SURGICAL DEBRIDEMENT followed by bactrim,metronidazole, linezolid or moxifloxacinSeptic arthritis: S. aureus, Group A Streptococcus, Pneumococcus, GCProsthetic joint – Coag. Neg Staph., S. aureusRecommendation: MRSA – Empiric = vanc, Confirmed = Dapto, Vanc or LzdGC = CeftriaxoneStreptococci = Pen or Ceftriaxone


Recommendations for Top 6 Infections3. MeningitisAdults and Children: Common – Pneumococcus and N. meningitidisRare – HIBRecommendation: Ceftriaxone and vancomycin for resistant pneumococcuNeonates and Elderly: Group B Streptococcus, Listeria, EnterobacteriaceaeRecommendation : Ampcillin plus ceftriaxone +/- gentamicin


Recommendations for Top 6 Infections4. Upper Respiratory TractAcute Sinusitis:Common – Pneumococcus, H. influenzae, M. catarrhalisRecommendation: amoxicillin or amox/clav, cefuroxime, cefpodoxime orlevofloxacin. Doxy or Bactrim for pen-allergicExacerbations of sinusitis: Same as above plus Pseudomonas in COPDRecommendation : Same as above plus cipro or ceftazidime for PseudomonasPharyngitis: Group A StreptococciRecommendation : Penicillin, amoxicillin or macrolide


Recommendations for Top 6 Infections5. PneumoniaCAP: Common – Pneumococcus, S. aureus, H. influenzaeAtypicals (Mycoplasma,Chlamydophila, Legionella)Recommendation:AMBULATORY: Azithromycin or Doxycycline orFluoroquinoloneHOSPITALIZED: Ceftriaxone plus macrolide orfluoroquinoloneIF SEVERE MRSA: Vanc, bactrim, linezolidHospital Acquired or VAP: GNR’s (Enterics, P. aeruginosa, Acinetobacter), S. aureusRecommendation : If no risk factors for MDR = ceftriaxone, levo or moxi,pip/tazoIf risk for MDR = pip/tazo, cefepime, carbapenem (not erta),vancomycin, linezolid, colistin or tigecycline(when options limited)


Recommendations for Top 6 Infections6. UTIUncomplicated: Common – E. coli, S. saprophyticus, other GNRs and enterococciRecommendation:Fluoroquinolones, bactrim, nitrofurantoin, amoxicillin orcephalosporinComplicated: Resistant GNR’s, S. aureus, enterococciRecommendation : OUTPATIENT - fluoroquinolone, amox/clav, oral 3 rd gen ceph(cefpodoxime, cefdinir, ceftibuten)INPATIENT – 3 rd gen ceph, fluoroquinolone, pip/tazo,carbapenem (not erta)


• Things you should know about susceptibilitytesting.• Brief (re)-introduction to primary classes ofantibiotics• Things to know and not test– Intrinsic resistance patterns• Don’t go there– Drug/site penetration discussion• What doesn’t belong?


When a doctor calls and asks…


Will you release this drug?


When a doctor calls and asks…YOUDOCTOR


Things to know and not test…OrganismSalmonella spp.Shigella spp.MRSAEnterococcus spp.Agents that Must not be reported assusceptible1 st and 2 nd generation cephalosporins,cephamycins and aminoglycosides1 st and 2 nd generation cephalosporins,cephamycins and aminoglycosidesPenicillins, beta-lactam/beta-lactamaseinhibitor combinations,cephalosporins** and carbapenemsAminoglycosides (except highconcentrations), cephalosporins,clindamycin and trim/sulfaLocation in CLSIM100-S21Table 2A, Page 42Table 2A, Page 42Table 2C, Page 68Table 2D, Page 84** Newer “fifth” generation cephalosporins (ceftobiprole and ceftaroline) haveactivity against MRSAWARNING: These antimicrobial agent/organism combinations may appear active invitro but are not effective clinically and should be reported as susceptible


Other interesting intrinsicresistance characteristicsVancomycin Resistant GrampositivesEnterococcus faecium• Not intrinsically resistantbut high percentage areVRE.ErysipelothrixLeuconostocPediococcusLactobacillusVancomycin Susceptible Gramnegatives• Chryseobacterium• Sphingomonas• Elizabethkingia


Other important intrinsicresistance characteristicsGRAM NEGATIVES• Stenotrophomonas maltophilia (metallobeta-lactamase)– All beta-lactam antibiotics (exceptaztreonam)• Klebsiella pneumoniae (class A betalactamase)– Ampicillin• Proteus mirabilis– Nitrofurantoin• Proteus vulgaris, Proteus penneri andMorganella– Piperacillin, ampicillincefoperazone (3 rd ) , cefuroxime(2 nd ), cefazolin (1 st )• Pseudomonas aeruginosa– Bactrim• Burkholderia cepacia, Pandorea,Ralstonia pickettii, GC, Neisseriameningitidis, Moraxella catarrhalis,Brucella, Proteus, Providencia andSerratia– Colistin• Aeromonas– Ampicillin• Achromobacter spp.– Aminoglycosides


Drug-Site Contraindications:Should not be routinely reported for bacteriaisolated from these sites• Oral agentsCSF• 1 st and 2 nd generationcephalosporins (exceptcefuroxime)• Cephamycins• Clindamycin• Macrolides• Tetracyclines• FluoroquinolonesRespiratory• DaptomycinUrine• Macrolides


Good resources• Medical letter- http://www.medicalletter.org/downloads/t94-1.pdf• Sanford Guide• CLSI document- M100 - Appendix• Manual of Clinical Microbiology“Antimicrobial Susceptibilities” sections• Clinical Microbiology Practices Handbook– Section 5 – procedure 5.16• http://labtestsonline.org


Glossary I and II• Class, subclass, generic name• Abbreviations / PO, IM, IV


Part 1Part 2CLSIM100-21PageGlossary ofAntimicrobial Agents


Questions?


Let’s review:Salmonella from blood cultureDrugAmpicillinCefazolinCefoxitinCefotaximeCiprofloxacinGentamicinInterpretationSusceptibleSusceptibleSusceptibleSusceptibleSusceptibleSusceptibleWhat is wrong with thisreport?• Cefazolin• Cefoxitin• Gentamicin


Let’s review:MRSA from blood cultureDrugPenicillinCefazolinOxacillinMeropenemVancomycinClindamycinBactrimInterpretationResistantResistantResistantSusceptibleSusceptibleSusceptibleSusceptibleWhat is wrong with thisreport?• Meropenem


Let’s review:Listeria monocytogenes from CSFDrugAmpicillinGentamicinCefotaximeDoxyclineClindamycinInterpretationSusceptibleSusceptibleSusceptibleSusceptibleSusceptibleWhat is wrong with thisreport?• Cefotaxime• Doxycycline• Clindamycin


Let’s review:Enterococcus faecium from CSFDrugAmpicillinGentamicin (High Level)CefotaximeBactrimClindamycinVancomycinInterpretationResistantSusceptibleSusceptibleSusceptibleSusceptibleResistatWhat is wrong with thisreport?• Cefotaxime• Clindamycin• Bactrim


Let’s review:ESBL producing Klebsiella pneumoniae from UrineDrugAmpicillinCefazolinCefalothinGentamicinCefotaximeTigecyclineCiprofloxacinCefepimeMeropenemClindamycinInterpretationResistantResistantResistantResistantResistantSusceptibleResistantResistantResistantSusceptibleWhat is wrong with thisreport?• Meropenem• Clindamycin

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