09 –Core Concepts: Antibacterial Drugs II Speaker: Helen Boucher, MD
Disclosures of Financial Relationships with Relevant Commercial Interests
•Editor - ID Clinics of North America - Antimicrobial Agents and Chemotherapy Core Concepts: Antibacterial Drugs II - Sanford Guide
• Treasurer, Infectious Diseases Society of America • Member, ID Board, American Board of Internal Medicine • Voting Member, Presidential Advisory Council on Combating Antibiotic Helen Boucher, MD, FACP, FIDSA Resistant Bacteria (PACCARB) Professor of Medicine Tufts University School of Medicine
Overview of Antibacterial Mechanisms To Orient You: Little is Testable Cell Wall Active Agents
• Penicillins • Cephalosporins • Carbapenems • Vancomycin • Daptomycin • Polymyxins
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β-lactam Antibiotics Share Mechanism of β-lactam Spectrum Action
— Why are there different spectrum of activity for Penicillins penicillins, cepahalosporins, carbapenems? Semi-synthetic penicillins Gram-positive 1st gen cephalosporins Broad and narrow susceptibility to beta- nd 2 gen cephalosporins lactamases 3rd gen cephalosporins Different penicillin binding proteins 4th gen cephalosporins Selective efflux pumps Carbapenems Gram-negative Ability to reach target site Monobactams
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©2021 Infectious Disease Board Review, LLC 09 –Core Concepts: Antibacterial Drugs II Speaker: Helen Boucher, MD
β-lactam Adverse Effects Penicillins Hidden-for reference only in syllabus Anaphylaxis / allergy Rx Spectrum Additional — See lecture by Sandy Nelson Adverse Seizures Events Penicillin Group A strep; Syphilis — Imipenem, cefepime (oral/IV) Myelosuppression, leukopenia, hemolytic anemia Oxacillin/nafcillin (IV) MSSA AIN Amoxicillin (oral) Amox and amp have similar spectrum and are both broader than penicillin Hypersensitivity hepatitis: e.g. Oxacillin Ampicillin (IV) More active against H. flu, E. coli, Enterococcus, Listeria Amoxicillin clavulanate Broader spectrum than amox/amp due to addn of a beta-lactamase Delayed Biliary stasis/sludging (oral) inhibitor; improved bioavilability (BID) hepatotoxicity Ampicillin sulbactam Some activity against S. aureus; more active against H. flu and other gram (amox/clav) — Ceftriaxone (IV) negatives due to stability to some beta-lactamases NOT active against Pseudomonas Renal Active against oral and gut anaerobes Piperacillin tazobactam Broader than amp/sulbactam — Interstitial nephritis (IV) Active against gram positive organisms including streptococci Broad activity against gram negatives incl Pseudomonas
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Question Cephalosporins Bactericidal What is the only cephalosporin active against — inhibit bacterial cell wall synthesis MRSA Time dependent killing Resistance due to susceptibility to β-lactamases A) Cefpodoxime Fewer allergic reactions than PCN B) Cefapime CSF penetration with third generation C) Ceftaroline Most renally excreted D) Cefixime E) Cefoxitin 9 10
Key Points About Cephalosporin Activity Cephalosporins
Rx Spectrum Additional Adverse Events Enterococci 1st Gen Ceph Staph and strep •Cefazolin MSSA — None are active •Cephalexin Some gram negatives including E. coli, Klebsiella, Proteus although 1st generation cephalosporins are very susceptible to beta-lactamases MRSA 2nd Gen Ceph Gram positive cocci •Cephamycin H. flu, E. coli, Klebsiella — Only ceftaroline active •Cefuroxime Cephamycin – active vs anaerobes, in vitro vs ESBLs (no clinical data) rd 3 Gen Ceph Streptococci pneumoniae (excellent) Biliary sludge Anaerobic activity •Ceftriaxone Gram negative rods but NOT Pseudomonas Excellent CSF penetration — Only Cephamycins active Drug of choice for bacterial meningitis th (e.g., cefoxitin, cefotetan) 4 Gen Ceph Broad gram positive and broad gram negative activity, including Pseudomonas Potential neurotoxicity, •Cefepime Often used as empiric therapy in hospitalized patients (however may need to especially in patients Now high levels of resistance add vancomycin to treat MRSA) with renal failure 5th Gen Ceph Broader than amp/sulbactam; ceftriaxone-like •Ceftaroline Prodrug Active against gram positive organisms including streptococci and broad activity against gram negatives not incl Pseudomonas 11 12
©2021 Infectious Disease Board Review, LLC 09 –Core Concepts: Antibacterial Drugs II Speaker: Helen Boucher, MD
Ceftaroline Fosamil – a Prodrug Ceftaroline Fosamil – a Prodrug (IV and IM, Not PO) (IV and IM, Not PO)
Activity Activity Active vs Gram-negative pathogens Gram-positive including MRSA and MDR S. pneumoniae E. coli, Klebsiella spp., H. influenzae (incl B-lactamase positive), M. catarrhalis Some activity vs E. faecalis; not E. faecium — Not Pseudomonas or ESBL+ GNB
Limited activity vs. anaerobes — Spectrum similar to ceftriaxone Active vs Cutibacterium (formerly Propionobacterim) acnes, Actinomyces spp. Bactericidal, time dependent killing
Lodise & Low, Drugs, 2012; Saravolatz et al. CID 2011: 52: 1156 13 Lodise & Low, Drugs, 2012; Saravolatz et al. CID 2011: 52: 1156 14
Ceftaroline Ceftaroline Clinical Use Safety and Monitoring Hypersensitivity 1-3%, rash 3% Acute bacterial skin and soft tissue infections GI - nausea, vomiting, diarrhea 5% Community Acquired Pneumonia Hematologic toxicity (class effect) — Eosinophilia S. aureus bloodstream infection — Positive Coomb’s test, rarely clinically significant — Controversial-see Chambers Lecture Hepatotoxicity – LFT abn 1-7% Controversy over dosing regimen Nephrotoxicity rare — 600mg twice daily – FDA-approved regimen Neurotoxicity – tremor, confusion, seizure, encephalopathy — Worse with renal failure
Lodise & Low, Drugs, 2012; Saravolatz et al. CID 2011: 52: 1156; File et al. CID 2010; 51: 1395; Zasowski et al, AAC 2017;61(2),e02015-16; Geriak et al. AAC 2019; 63(5); Kalil et al. AAC 2019; 63(11) 15 16
Vancomycin Vancomycin Resistance
Bactericidal (slowly) VISA — inhibits bacterial cell wall synthesis Active against: — Thick walls, generous binding sites… — Gram Positive Aerobes Vancomycin resistance Streptococcus — Not in Streptococcus Staphyloccus — RARE in Staphylococcus Enterococcus — Common in Enterococcus — Gram Positive Anaerobes Rare in E. faecalis (4% in 2014) Clostridia Common in E. faecium (71% in 2014) Propionibacteria Mechanism Peptostreptococci Change in vancomycin binding site on peptidoglycan Actinomyces 17 18
©2021 Infectious Disease Board Review, LLC 09 –Core Concepts: Antibacterial Drugs II Speaker: Helen Boucher, MD
Vancomycin for MRSA Bloodstream Infection Vancomycin ADRs / Interactions Controversy re: optimal therapy –see Dr. Chambers lecture Adverse Drug Reactions Drug Interactions Vancomycin trough only monitoring no longer recommended Nephrotoxicity Increased nephrotoxicity when — Target AUC/MIC ratio of 400 to 600 BMD — Duration > 14d given with other nephrotoxins (assume vancomycin MICBMD = 1 mg/L) — Dose > 4g / day — Aminoglycosides Loading dose for seriously ill adults — Trough > 20 — NSAIDs — 20–35 mg/kg can be considered Ototoxicity — Contrast — Pediatric doses higher Histamine Release Syndrome — Cyclosporine — Tacrolimus 60-80 mg/kg/day divided q 6-8 hours — Loop Diuretics — ACE inhibitors Dosing Calculator helps!
https://www.idsociety.org/practice-guideline/vancomycin/ 19 20
Daptomycin (IV) Daptomycin for S. aureus Bacteremia and Right IE
Antimicrobial Class: Lipopeptide Pneumonia — Do not use: surfactant binding inactivates drug Broad spectrum gram + activity
— Including MRSA Monitoring Rapidly bactericidal — CPK twice weekly Concentration-dependent killing — Discontinue if myopathy or CPK> 5x ULN Indications Toxicity — Eosinophilic Pneumonia — cSSSI Rx supportive care and steroids — S. aureus bloodstream infection — Falsely prolonged Prothrombin Time — Right-sided endocarditis — Muscle inflammation CPK increase, myopathy, myositis Risk factors: renal failure, statins, obesity Fenton C et al. Drugs 2004; 64: 445-55, Tedesco KL, Rybak MJ. Pharmacother 2004; 24:41-57, Mangili A et al. Clin Infect Dis 2005; 40:1058-60, Fowler VG et al. New Engl J Med 2006; 355:653-665 21 22
Oritavancin and Dalbavancin Vancomycin and Daptomycin Long Acting Glycopeptides Drug MOA MOR Spectrum Adverse Event Mechanism of Action Vancomycin Inhibits cell wall Change in cell Gram positive • Histamine — Similar to vancomycin synthesis (not a wall terminus cocci only release — Inhibition of cell wall synthesis beta lactam) from D-ala-D-ala including MRSA syndrome to D-ala-D- • Kidney Dosing lactate (high level toxicity — Oritavancin: IV only: 1 dose (1200 mg over 3hours) resistance) — Dalbavancin: IV only: 1000mg, then 500mg every 7 days …..OR 1500mg x 1 Daptomycin Cell membrane • Decreased Resistant gram • Skeletal Approved depolarization binding of positive cocci muscle drug to cell including MRSA toxicity — Skin and Soft Tissue Potassium efflux membrane and VRE — Oritavancin FDA warning against use in osteomyelitis • Altered cell membrane Inactivated by — Dalbavancin also used for osteomyelitis, right sided endocarditis potential surfactant (not Toxicity used for — Oritavancin prolongs aPTT (artificially), PT, and activated whole blood pneumonia) clotting time (ACT) for 5 days 23 24
©2021 Infectious Disease Board Review, LLC 09 –Core Concepts: Antibacterial Drugs II Speaker: Helen Boucher, MD
Oritavancin - Lipoglycopeptide With Long Half-life Dalbavancin - Lipoglycopeptide With Long Half-life
Mechanism of action Gram-positive spectrum — inhibition of cell wall synthesis and disrupts bacterial membrane — Gram-positive spectrum — S. aureus, MRSA, VISA, GAS S. aureus, MRSA, VISA, VRSA, GAS, S. anginosus group — Low MRSA MICs E. faecalis , E. faecium/VRE (active vs VanA, VanB, Van C, Van D) — Enterococci – inactive vs VanA Bactericidal Mechanism of action – cell wall synthesis inhibit IV only, 1 dose Bactericidal — 1200 mg over 3 hours IV only ( dose over 30 min), long half-life (app 8.5 days) Cytochrome P450 enzyme – warfarin interaction Dosing FDA approved — 1000mg, then 500mg every 7 days OR 1500mg x 1 — ABSSSI — Decrease dose by 25% for CrCl <30ml/min, not dialysis FDA approved ABSSSI
Dowell et al. Critical Care 2008, 12(Suppl 2):P26. www.fda.gov HF Chambers NEJM 2014; 370(23): 2238. WWW.FDA.GOV, Nailor and Sobel. Infect Dis Clin N Am 23(2009): 965. Jauregui et al. CID 2005; 41: 1407; Dunne et al CID 2016 Arias et al CID 2012: 54 (Suppl 3): S233; GR Corey et al. NEJM 2014; 370(23): 2180-2190 25 HW Boucher, M Wilcox, GH Talbot, S Puttagunta, AF Das, MW Dunne. NEJM 2014; 370(23): 2169 26
Lipo/glycopeptide Testable Toxicities Dalbavancin Other uses Vancomycin: Nephrotox.; Histamine Release — Limited data, varying dosing regimens Daptomycin: CPK elevation, myopathy, Endocarditis and osteomyelitis rhabdomyolysis; Eosinophilic pneumonia Persons who inject drugs Telavancin: Nephrotoxicity Case reports of failure with emergence of VISA, Oritavancin: LFT elevation; False prolongation of presumably associated with low-level drug exposure aPTT — One patient had VISA detected in urine while on dalbavancin for CLASBI Dalbavancin: LFT elevation — One patient was pregnant and had failure of therapy for IE
Steele JM et al. J Clin Pharm Ther. 2018;43:101-103. Werth BJ et al. Clin Microbiol Infect. 2018;24:429.e1-429.e5. 27 28
Question Antibiotics Active Intracellularly
Which quinolone has activity against MRSA Fluoroquinolones Tetracyclines A) Ciprofloxacin Linezolid B) Moxifloxacin TMP/SMX C) Trovafloxacin Pleuromutilins D) Delafloxacin E) Levofloxacin
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©2021 Infectious Disease Board Review, LLC 09 –Core Concepts: Antibacterial Drugs II Speaker: Helen Boucher, MD
Fluoroquinolones Fluoroquinolone Mechanism of Action Spectrum of Gram Positive Activity
Topoisomerase inhibitors Gram-positive Gram-negative Anaerobes Cipro Poor strep Best FQ for Some — Inhibits DNA gyrase and topoisomerases II and IV Some MSSA •Pseudomonas — Gyrase more for gram negs, topos for gram pos •E coli Resistance Levo Good strep Best for Stenotrophomas Some — Target site mutations Some MSSA — Drug permeability mutations
— Occurs spontaneously on therapy Moxi Good strep Not effective Best Good MSSA Don’t use for UTI
Dr. Gilbert will address Gram-negative activity 31 32
Fluoroquinolone Pharmacokinetics Fluoroquinolone Adverse Effects
High oral bioavailability C. difficile Arthropathy/cartilage toxicity / tendonitis — >95% for moxi / levo, 70-80% for cipro — FDA Warning for rare tendon rupture Widely distributed to tissues Increased risk: advanced age, poor renal function, concomitant steroids — Lower than serum but therapeutic concentration in CSF, Altered mental status (HA, dizziness, insomnia) saliva, bone, and ascitic fluid Dysglycemia-FDA warning especially for older adults and diabetics Elimination — Hypo and hyperglycemia Aortic aneurysm and aortic dissection-FDA warning — Levo / cipro: renal through tubular secretion — Association is controversial — Moxi: >60% hepatic/ biliary unchanged QTc Prolongation: Moxi > levo ? Cipro — Increased risk: Concomitant QTc prolongers, cardiomyopathy, bradycardia, low K+ and Mg++ 33 34
Delafloxacin Tetracyclines: Major Clinical Uses
Broad spectrum fluoroquinolone • Acne (minocycline) • Respiratory tract infections Potential advantages: – Atypical pneumonia — MRSA activity • Sexually Transmitted Diseases — Broad spectrum including Pseudomonas – Syphilis (T. pallidum) –alternative therapy Dosing IV and oral twice daily – Chlamydia spp. Approved for skin and soft tissue infections • Tick‐Borne Illnesses – Lyme disease – Anaplasmosis – Ehrlichiosis – Rocky Mountain Spotted Fever • Community Acquired MRSA infections
Saravolatz LD and Stein GE. Clin Infect Dis. 2019;68(6):1058–62 35 36
©2021 Infectious Disease Board Review, LLC 09 –Core Concepts: Antibacterial Drugs II Speaker: Helen Boucher, MD
Tetracyclines: Adverse Effects New Tetracyclines Gastrointestinal Omadacycline Eravacycline — Nausea FDA approval ABSSSI, CABP cIAI, not cUTI (failed studies) — Esophageal ulceration Dosing 200 mg loading dose over 60 min day 1, 1mg/kg IV q 12h (over 60 minutes) 100mg IV over 30 min or 300mg orally — Hepatotoxicity once daily Skin No dose adjustment for renal/hepatic Dose adjustment with hepatic — Photosensitivity impairment impairment Children Activity Broad spectrum: Gram-pos including MRSA, VRE; Yellow brown tooth discoloration if age <8 yrs for tetracyclines Gram-neg including ESBL, CRE (not all); anaerobes Doxycycline therapy OK for ≤21 days in children of all ages Issues Limited activity vs carbapenem-resistant High MIC Pseudomonas, Burkholderia Ref: Redbook 2018 and Am Academy Pediatrics K. pneumoniae spp. Pregnancy Safety GI, rash, ?heart rate GI, rash — Tetracyclines cross the placenta; accumulate in fetal bone/teeth — Most tetracyclines contraindicated in pregnancy 37 38
Linezolid and Tedizolid Question Oxazolidinone Drug Class
Mechanism What is the major advantage of tedizolid — binds 50s ribosome/prevents formation of initiation complex compared to linezolid Spectrum of activity — Gram positive cocci including MRSA and VRE A) Longer half life Linezolid resistant Staph aureus reported B) Better penetration of prostate — Mycobacteria Resistance is rare; target change C) Better CSF Penetration Linezolid bid; Tedizolid qd D) Wide spectrum of activity against anaerobes FDA approvals for Linezolid: — Skin and Soft Tissue, Pneumonia, VRE E) More effective in clinical studies for VRE — NOT Bloodstream infection (Black Box Warning)
Shinabarger DL et al. Antimicrob Agents Chemother 1997; 41: 2132-36; Swaney Sm et al. Antimicrob Agents Chemother 1998; 42: 3251-55; 39 French G. Int J Clin Pract 2001; 55: 59-63 40
Tedizolid - Oxazolidinone Drug Class Linezolid Adverse Events Once Daily Dosing, Lower Dose Non-antibiotic antibacterial; a MAO inhibitor Adverse events related to mitochondrial toxicity: — Inhibits protein synthesis, bactreiostatic Binds peptidyl transferase region of bacterial ribosome — Cytopenias prevents binding of amino acyl tRNA Gram-positive spectrum Monitor CBC — S. aureus, MRSA, VISA, GAS, S. agalactiae, S anginosus group, E. faecalis (vanco-susceptible only) — Peripheral and optic neuropathy IV and oral — Rare: Half-life 12 hours, once daily dosing Lactic acidosis, serotonin syndrome (w SSRIs) 200 mg daily x 6 days — No dose adjustment mortality with catheter-associated bacteremia for age, renal/hepatic impairment FDA approved ABSSSI HABP/VABP Study Failed
Tsiodras S et al. Lancet 2001;358: 207-208; Pillai SK et al. Clin Infect Dis 2002; 186: 1603-7; Wilson P et al. J Antimicrob Chemother 2003;51:186-88; Medwatch March 16, 2007 Moellering CID January 2014; www.fda.gov; Prokocimer et al. JAMA 2013; 41 Moran GJ, et al. Lancet Infect Dis. 2014;14:696-705; CID 2021 42
©2021 Infectious Disease Board Review, LLC 09 –Core Concepts: Antibacterial Drugs II Speaker: Helen Boucher, MD
Sulfonamides & TMP/SMX TMP/SMX Mechanism of Action
st Together inhibit folic acid synthesis 1 clinically used antibiotic: sulfanilamide PABA + THA Sulfamethoxazole — Identified as anti-streptococcal in 1932 — Competitively inhibit incorporation Dihydropteroate of para-amino benzoic acid (PABA) synthetase — Initially an industrial dye into tetrahydropteroic acid (THA) Dihydropteroic acid — Changed the face of WWII SMX has higher affinity for THA Dihydrofolate than PABA does synthetase Combined with trimethoprim 1968 Trimethoprim Dihydrofolic acid Dihydrofolate — Inhibits dihydrofolate reductase Off-shoot: methotrexate (DFHR) reductase Tetrahydrofolic acid — Used for various hematologic, oncologic, and — 50,000 to 100,000 times more active against bacterial DFHR than human rheumatologic conditions enzyme Thymidine Methionine Purines 43 44
TMP/SMX Resistance Mechanisms TMP-SMX Adverse Effects
Sulfamethoxazole Trimethoprim • Anaphylaxis • Gastrointestinal effects PABA overproduction Novel plasmid-mediated DFHR • Skin rashes • “Nephrotoxicity” — Caution with OTC PABA Altered cell permeability • Bone marrow toxicity • Fever supplements Loss of binding capacity • Kernicterus • Drug-drug interactions Structurally mutated Overproduction of or alterations • Hemolysis (G6PD def) • Hyperkalemia dihydropteroate synthetase in dihydrofolate reductase Decreased bacterial cell • Hepatitis permeability HIGH PLASMA COMPETES FOR PROTEIN BINDING TUBULAR SECRETION
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TMP/SMX Spectrum of Activity - Typical Bugs TMP/SMX Spectrum of Activity - Odd Bugs
Gram Positive Stenotrophomonas maltophila — Staphylococci: great Listeria monocytogenes — Streptococci: controversial Nocardia — Enterococcus: not effective Moraxella catarhallis Gram Negative Pneumocystis jirovecii — E. coli: ok, increasing resistance Toxoplasmosis gondii (but not superior to pyr/sulf) — Enterobacterales: relatively effective Chlamydia (but enough resistance that its not used for STDs) — Pseudomonas / Acinetobacter: not effective Atypical mycobacteria — Stenotrophomonas: often drug of choice
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©2021 Infectious Disease Board Review, LLC 09 –Core Concepts: Antibacterial Drugs II Speaker: Helen Boucher, MD
Macrolides (Erythro, Clarithro, Azithro) Lefamulin Protein Synthesis Inhibitor Binds 50s Ribosome
Pleuromutilin antibiotic with IV and PO formulation Spectrum: — Protein synthesis inhibitor CABP Pathogens: Strep Pneumo Resistance — Bacteriostatic Streptococcus pneumoniae Rising rates in US FDA Approved community acquired bacterial pneumonia Haemophilus influenzae — Don’t use macrolides — Non-inferior to moxifloxacin for CABP in two studies Moraxella catarrhalis if local rates of 5 days of po lefamulin vs. 7 days of po moxifloxacin Leigonella spp. resistance > 25% C. pneumoniae Streptococcus groups A, C, and G
File CID 2019 49 50
Macrolide Spectrum Macrolide Adverse Drug Reactions STDs Miscellaneous Bugs QTc Prolongation — Ery ≥ clarith > azith Haemophilus ducreyi Arcanobacter spp. (chancroid) Bartonella henselae (cat- GI intolerance: nausea, bloating, diarrhea Chlamydia spp. scratch) — Ery >> clarith >> azith Bordetella pertussis — Dose related GI pathogens Atypical mycobacteria — Activity at motilin (peristalsis) receptors Campylobacter spp. Borrelia burgdorferi — Rare cholestatic hepatitis Helicobacter pylori Babesia microti Pregnancy risk Salmonella typhi Shigella spp.
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Clindamycin Adverse Events Clindamycin
Mechanism of action Allergic reactions: — Protein Synthesis Inhibitor — Rash, fever, erythema multiforme, anaphylaxis — Binds 50s Ribosome Elevated AST/ALT — rare progression to severe liver injury Diarrhea — can cause severe C. difficile toxin-mediated colitis Reversible neutropenia, thrombocytopenia, and eosinophilia Taste disturbance
Sanford Guide, Brit J Clin Pharmacol 64:542, 2007; Clin Med Insights Case Rep 2019 Dec 25;12:1-4 53 Clin Infect Dis. 2014; 59:698-705J Antimicrob Chemother. 2019 Jan 1;74(1):1-5 54
©2021 Infectious Disease Board Review, LLC 09 –Core Concepts: Antibacterial Drugs II Speaker: Helen Boucher, MD
Protein Synthesis Inhibitors - Summary
Drug Mech of Mech of Resist Spectrum Clinical Uses Major Adverse Effect Thank You! Action Linezolid 50s Mutation in ribosome Gram + (resistant) MRSA, VRE Pancytopenia Henry Masur Kenneth Lawrence Serotonin syndrome Sue Cammarata Evan Loh Tetracyclines 30s Target site modification Comm acq MRSA, atypical Lyme, RMSF, Enamel hypoplasia, (Doxycyline) pneumonia pathogens, Comm Acq MRSA, photosensitivity G. Ralph Corey Paul McGovern Efflux Lyme, rickettsia and other acne, CABP Esophageal ulceration Sara Cosgrove Federico Perez tick borne pathogens, Treponema pallidum Mike Dudley Debra Poutsiaka Aminoglyco- 30s Inactivating enzymes GNRs serious gram Nephrotoxicity sides negative infx Oto-vestib toxicity Mike Dunne George H. Talbot Efflux David Gilbert Ribosomal mutations Susan Hadley Macrolides 50s Target site modification Gram + Atypical pneumonia, p450 drug interactions Atypical PNA pathogens resp infx GI upset Teena Kohli Efflux QT prolongation Clindamycin 50s Target site modification Gram +, Anaerobes Oral and intra-abd C. difficile colitis Our patients and their infx families Efflux
Inactivate drug 55 56
Questions, Comments?
@hboucher3 [email protected] [email protected]
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