PY1 Antibiotics 2024 (1) PDF

Antibiotics “Broad-spectrum antibiotics are not a substitute for rational thought” – Anon. Jason C. Gallagher, Pharm.D., FCCP, FIDP, FIDSA, BCPS 1 Graphic: CDC Clinical Professor ...

Antibiotics “Broad-spectrum antibiotics are not a substitute for rational thought” – Anon. Jason C. Gallagher, Pharm.D., FCCP, FIDP, FIDSA, BCPS 1 Graphic: CDC Clinical Professor  Objectives At the conclusion of the lectures, the student should be able to: Describe key characteristics of the classes of antibiotics including their: Spectra of activity Basic pharmacokinetic profile Major adverse effects Explain the mechanisms of action of the classes of antibiotics discussed Determine which antibiotics are likely to be useful for a given clinical scenario (a 2  Objectives You WILL NEED to be You WILL NOT need to able to: know: Choose an antibiotic Uses based on an Structures infection’s organism or typical organisms This means relating the antibiotics to the organisms you have already learned. Choose an antibiotic to avoid toxicity in a patient 3  Glossary IV- intravenous UTI- urinary tract PO- per os (oral) infection GI- gastrointestinal MOA- mechanism of AE- adverse effect action MDR- multidrug PUD- peptic ulcer disease resistant CYP450- cytochrome t 1/2 – half-life P450 BP- blood pressure N/V/D- PMH- past medical nausea/vomiting/diarr history hea SICU- surgical CNS- central nervous intensive care unit system 4  Glossary SSTI- skin and soft MSSA/MRSA- tissue infection methicillin- SSSI- skin and skin susceptible/resistant structure infection Staphylococcus URI/URTI- upper aureus respiratory (tract) VRE- vancomycin- infection resistant Enterococcus PBP- penicillin-binding CAP- community- protein acquired pneumonia PCN- penicillin HAP- hospital-acquired pneumonia 5  A: moderate Super brief D: wide The Key pharmacokinetic summary E: renal A = absorption D = distribution E = elimination Antibiotics highlighted in GREEN are the ones important to know/most commonly used Antibiotics crossed off are not used, but may be historically relevant Antibiotics underlined are available orally Antibiotics italicized are intravenous – I won’t ask you what is oral and what is 6  General Approach to Infectious Diseases Suspect infection Culture suspected sites EMPIRIC THERAPY for likely pathogens Stain sample Identification Susceptibilities Gallagher JC, MacDougall CM. 7 Antibiotics Simplified, 5th ed. Jones & DEFINITIVE THERAPY  Fundamental Antibiotic Mechanisms of Action Cell Wall Synthesis Cell Membrane Function Folic Acid Synthesis DNA Synthesis Protein Synthesis and Function 8  Spectrum of Activity The Chart MRS E. VR MSS Stre “S” “R” Pseudomon Anaerob Atypica E A faecal A p is GNRs GNRs as es ls 🔑 9 a  Methicillin- resistant Methicillin- Staphylococcus susceptible Spectrum of Activity aureus is resistant to many Staphylococcus aureus is drugs The Chart susceptible to many beta- MRS lactams E. Pseudomon VR MSS Stre “S” “R” Anaerob Atypica E A faecal as A p is GNRs GNRs es ls 🔑 This refers Refers to to E. Enterococ faecium cus primarily faecalis only, not E. faecium This refers to many streptococci, including viridans group strep, S. pneumoniae, S. pyogenes, and S. agalactiae 10 a  Intracellular Spectrum of Activity organisms (Legionella, Haemophilus influenzae Moraxella catarrhalis The Chart Mycoplasma, Chlamydia etc) E. Pseudomon VR MRS MSS Stre “S” “R” Anaerob Atypica Enterobacterales faecal as E A A pthat are is GNRs GNRs es ls drug-susceptible, eg: Escherichia coli Some Klebsiella spp Salmonella Resistant GNR that Gut Enterobacterales that are drug- relatively anaerobe resistant few drugs s are active (Bacteroid Includes beta-lactamase-producing against es, strains of: Fusobacteri Enterobacter um, etc) Escherichia coli Klebsiella Does Citrobacter NOT Proteus include Serratia C. And others difficile 11 a  Spectrum of Activity The Chart E. VR MRS MSS Stre “S” “R” Pseudomon Anaerob Atypica faecal E A A p is GNRs GNRs as es ls Caveats: Coverage is general and not a universal truth Depth of coverage is not indicated well here Differences between drugs within a class often exist Differences between species within a category often exist (e.g. between E. coli and Enterobacter cloacae) Not every organism is here 12 a Inhibitors of Cell-wall Synthesis 13  The Cell Walls of Gram-Positive and Gram-Negative Organisms are Different Sherris Medical Microbiology, 5th edition. 14 Gallagher JC, MacDougal C. Antibiotics Simplified, Cell wall syn diagram 15 a  Beta-lactams Penicillins Cephalosporins – Natural – 1st generation – Antistaphylococcal – 2nd generation – Aminopenicillins – 3rd generation – Antipseudomonal – 4th generation – Penicillin + beta- – Antistaphylococcal lactamase inhibitor Carbapenems combinations Monobactam 16  Beta-lactam Structures Beta-lactam ring (“B”) is conserved across classes Different substitutions change drug properties 17 PBP PBP PBP PBP PBP = penicillin-binding proteins PBP (which include transpeptidases) 18  Beta-lactams cause bacterial suicide 19 ino T and Nakazawa S. Antimicrob Agents Chemother 1976;9:1033-42.  Beta-lactams More Similar than Different Similarities Differences Mechanism of action Absorption Good tissue penetration Hydrophilicity Pharmacodynamics Types of PBPs targeted Renal elimination Stability against (mostly) enzymatic degradation Short half-lives Bactericidal (mostly) Class adverse effects: hypersensitivity, nausea, diarrhea, hemolytic effects 20 First there was penicillin… 21 a  A: moderate D: wide Natural Penicillins E: renal Penicillin G (benzylpenicillin), Penicillin V, Penicillin G Penicillin G benzathine PCN G – IV only PCN V – PO only PCN G benzathine – IM only Renal elimination 22 Natural Penicillins Very short half- lives (~30 minutes) – Frequent dosing required Useful spectrum: streptococci, enterococci, Treponema pallidum Benzathine PCN Main uses: can be FATAL if susceptible given IV! streptococcal 23  Then Came Staphylococcal Resistance “It is not difficult to make microbes resistant to penicillin in the laboratory by exposing them to concentrations not sufficient to kill them, and the same thing has occasionally happened in the body.” - Sir Alexander Fleming, 1945 24 hoto: http://en.wikipedia.org.  Beta-lactamases Normal enzyme, leads to cross-linking Resistance enzyme, destroys drug 25 ucation in Chemistry, July 2009. a 26  A: poor Antistaphylococcal D: wide E: hepatic Penicillins aka Penicillinase- resistant Penicillin G penicillins Methicillin, Nafcillin, Oxacillin, Dicloxacillin Contain bulky R Oxacillin group that inhibits many beta- 27 lactamases  Antistaphylococcal Penicillins Methicillin removed from market many years ago due to adverse effects Nafcillin and oxacillin are hepatically eliminated Useful spectrum: MSSA, streptococci Main use: susceptible staphylococcal infections (e.g.Susceptibility to one = Note: cellulitis, endocarditis) susceptibility to ALL antistaphylococcal beta-lactams 28 29 But what about Gram negatives? 30  A: moderate D: wide Aminopenicillins E: renal Ampicillin, Amoxicillin Penicillin G Susceptible to beta-lactamases Amino group confers improved Ampicillin Gram-negative activity Amoxicillin 31 a  Amoxicillin is Better Absorbed than Ampicillin X = amoxicillin O = ampicillin Gordon RC et al. Antimicrob Agents Chemother 1972;1:504-7. 32 Klimek JJ et al. J Infect Dis 1977;135:999-1002.  Aminopenicillins Both ampicillin and amoxicillin are available PO, but amoxicillin has much better bioavailability Useful spectrum: streptococci, enterococci, some enteric GNRs that don’t produce beta- lactamases, Listeria, H. pylori Main uses: URIs, 33 peptic ulcer disease,  What about Pseudomonas? 34 es: wikipedia.org, learningradiology.com, textbookofbacteriology.com  A: poor D: wide Antipseudomonal Penicillins E: renal Two types Penicillin – Ureidopenicillins Piperacillin – No longer available as a Ampicillin single agent Mezlocillin Azlocillin – Carboxypenicillins Carbenicillin Ticarcillin Penetrate cell wall of Piperacillin Pseudomonas (unlike aminopenicillins) 35 Antipseudomonal Penicillins Additional AE: thrombocytopenia Susceptible to beta-lactamases Useful spectrum: as aminopenicillins, plus Pseudomonas, better coverage vs. GNR Main uses: None – Only piperacillin still used, in combination with 36  A: variable Penicillin/Beta-Lactamase D: wide E: renal Inhibitor Combinations Piperacillin/ Tazobactam Tazobactam (Zosyn®) Ampicillin/Sulbactam (Unasyn®) Sulbactam Amoxicillin/ Clavulanate (Augmentin®) Clavulanate 37  Penicillin/Beta-Lactamase Inhibitor Combinations Useful spectrum = parent drug + most beta-lactamase producing bacteria – Streptococci, MSSA, enterococci – Better GNR coverage than parent drugs alone – Anaerobes Amp/sulbactam and amox/clav are Note: Susceptibility not active to one = vs. Pseudomonas susceptibility to ALL antistaphylococcal beta-lactams 38  Penicillin/Beta-Lactamase Inhibitor Combinations Broad spectrum leads to good empiric coverage for nosocomial organisms Main uses: GI infections, abscesses, HAP, serious nosocomial infections, diabetic wound infections 39 40  Penicillin Drug Development Natural PCNs Better against Better against GNRs Staphylococcus Anti-staph PCNs Aminopenicillins Antipseudomonal PCNs Penicillin/Beta-Lactamase Inhibitor Combinations 41 llagher JC, MacDougall C. Antibiotics Simplified, 5 ed. 2023. th a  Spectrum of Activity Penicillins E. VR MRS MSS Stre “S” “R” Pseudomon Anaerob Atypica faecal E A A p is GNRs GNRs as es ls Natural PCNs Anti-staph PCNs Aminopenicillins Antipseudo Antipseudomonal PCNs monal PCNs PCN/Beta-Lactamase Inhibitor Combinations Amp/sul (ampicillin/sulbactam, amox/clav) amox/cla Piperacillin/Tazobactam 42 a  Case JT is a 21 YO WF with no significant PMH who is sexually active. She comes to clinic with a 2-day history of flank pain, mild fevers, and frequent, painful urination. A urinalysis is performed and is positive, and she is to be treated for pyelonephritis, which is most Talk to a neighbor and look at your frequently caused by E. coli. notes so far to find the best answer. 43 44  Case BD is a 63-year-old man with a PMH of HTN and poorly controlled diabetes. He presents to the ED with an ulcer on the sole of his right foot this is oozing pus and smells foul, which indicates the presence of anaerobic bacteria. Surgery is called to evaluate the wound, and antibiotics are to be initiated for the GPCs andTalkGNRs to a neighbor that areand look at your likely notes so far to find the best answer. present. 45 /www.orthobullets.com/foot-and-ankle/7046/diabetic-foot-ulcers 46  Cephalosporins Evolving through Generations 47  Cephalosporins All have six- membered (vs five for PCNs) ring attached to beta- lactam ring All have same MOA as other beta-lactams Less beta- lactamase Note: Susceptibility to one = susceptible than susceptibility to ALL most penicillins antistaphylococcal beta-lactams48  A: moderate 1 Generation st D: wide E: renal Cephalosporins Cefazolin, Cephalexin, Cefazolin Cefadroxil Cephalexin 49  1st Generation Cephalosporins Eliminated renally Useful spectrum: MSSA, streptococci, some GNR Main uses: surgical prophylaxis, cellulitis, UTIs 50  A: variable D: wide 2nd Generation Cephalosporins E: renal Cefuroxime, Cefoxitin, Cefotetan, Cefaclor, Cefamandole, Cefuroxime Cefprozil, Cefonocid, Loracarbef, Ceforanide 51  2nd Generation Cephalosporins Somewhat worse Gram-positive (staph/strep) coverage compared to 1st gen cephs, but somewhat better Gram-negative coverage Cefotetan and cefoxitin have anaerobic activity Main uses: URTIs, surgical prophylaxis 52  A: variable D: wide 3rd Generation Cephalosporins E: renal/biliary Ceftriaxone, Cefotaxime, Ceftriaxone Ceftazidime, Cefdinir, Cefixime, Cefpodoxime, Moxalactam, Ceftazidime Ceftizoxime, Ceftibuten, Cefoperazone 53 3rd Generation Cephalosporins Compared to 2nd generation cephalosporins – Decreased antistaphylococcal activity – Better antistreptococcal activity – Exceptions: ceftazidime, cefixime, which have little or no useful Gram- positive coverage – Better Gram-negative coverage – Ceftazidime is active vs. Pseudomonas aeruginosa 54  3rd Generation Cephalosporins Eliminated primarily renally, except ceftriaxone and cefoperazone – Ceftriaxone has dual elimination and can cause biliary sludging in neonates Don’t give to neonates! Main uses: meningitis, CAP/HAP, Lyme disease, abdominal infections, serious UTIs 55  Biliary Sludging ge: Wikipedia.org. Just the image though, I’m not crazy. 56 HW et al. Sub-Saharan Afr J Med 2016;3:210-16.  A: poor 4 Generation th D: wide E: renal Cephalosporin Cefepime Eliminated renally Useful spectrum: MSSA, streptococci, GNR including Pseudomonas Main uses: HAP, nosocomial infections 57  A: poor D: wide Anti-MRSA Cephalosporin E: renal Ceftaroline – Anti-MRSA cephalosporin – Useful spectrum: MRSA and MSSA, streptococci, enteric GNR – Not useful vs Pseudomonas – Susceptible to some beta-lactamases 58 Cephalosporin/beta- A: poor D: wide lactamase Inhibitor E: renal Combinations Ceftolozane/ Ceftazidime/ tazobactam avibactam Ceftolozane – 3rd Ceftazidime – 3rd generation generation cephalosporin with cephalosporin enhanced potency (antipseudomonal) against Pseudomonas Avibactam – Novel – Avoids common beta-lactamase mechanisms of inhibitor that prevents resistance destruction from most Tazobactam – prevents beta-lactamases destruction of Strong against GNRs, ceftolozane by many particularly Klebsiella beta-lactamases What you need to know: They kill the really pneumoniae and 59 Cefiderocol A: poor D: wide E: renal Siderophore Cephalosporin Drug that combines cephalosporin structure with a siderophore, which binds to iron and is transported into bacteria actively Activity: GNRs, including P. aeruginosa and other highly- What you need to know: It kills the really resistant60 resistant GNRs  Cephalosporin Groups Cefazolin Most 1st Useful Against Gram-positive Cefuroxime GPCs Gram-negative 2nd activity Ceftriaxone Most activity Useful 3rd Against Resistant Ceftazidime GNRs Useful against MRSA 61 Cefepime  Spectrum of Activity Cephalosporins E. VR MRS MSS “S” “R” Pseudomon Anaerob Atypica E Strep faecal A A is GNRs GNRs as es ls 1st 1st Generation Gen Cephs Cephs Cefot 2nd Gen 2nd Gen etan, Cephs Cephs cefoxi tin 3rd Gen 3rd Gen Cephs Cephs Ceftazidime, Ceftolozane (3rd gen) Cefepime (4th Cefepime (4th Gen Ceph) Gen Ceph) Anti-MRSA Ceph Anti-MRSA (Ceftaroline) Ceph Cefiderocol 62 a  A: poor D: wide Monobactam Aztreonam E: renal Only active vs. GNR, including Pseudomonas Renally eliminated Not cross-reactive with Penicillin G other beta-lactam allergies, except ceftazidime and cefiderocol Main use: Gram- negative infections in patients with allergies to other beta-lactams Aztreonam 63  A: poor D: wide Carbapenems E: renal Imipenem/ Cilastatin, Meropenem, Penicillin G Ertapenem Renally eliminated Imipenem Additional AE: imipenem higher incidence of seizures Meropenem 64  Carbapenems Stable to most beta-lactamases – BUT carbapenemases exist (of course!) Should not be first-line agents for most uses Useful spectrum – Imipenem, Meropenem – MSSA, streptococci, E. faecalis, anaerobes – Many GNR, including P. aeruginosa Useful spectrum – Ertapenem – As above, Note: Susceptibility to one except inactive vs. = enterococci, P. aeruginosa, Acinetobacter susceptibility sp. to ALL antistaphylococcal beta-lactams 65  Carbapenems Main uses: nosocomial infections, mixed aerobic/anaerobic infections, resistant infections – Use of these drugs continues to increase due to resistance to other agents 66  Carbapenem/Beta- A: poor D: wide lactamase Inhibitor E: renal Combinations Meropenem Agents: meropenem- vaborbactam, imipenem-(cilastatin)- relebactam Vaborbactam Spectrum: As meropenem and imipenem, plus Imipenem activity against highly resistant Relebactam What you need to know:Enterobacterales They kill the really 67  Spectrum of Activity Carbapenems and Aztreonam E. VR MRS MSS “S” “R” Pseudomon Anaerob Atypical E Strep faecali A A s GNRs GNRs as es s Imipenem, Meropenem Ertape Ertapenem Ertapenem nem Aztreonam Meropenem/vaborbactam, Imipenem-relebactam 68 a  Hypersensitivity Reactions Typ Mediator Reaction Effects e Anaphylaxis, I IgE Immediate angioedema, urticaria, bronchospasm Non- Cellular destruction II IgG/IgM immediate (hemolytic anemia) Antigen/ Non- III antibody Serum sickness immediate complexes Non- Contact hypersensitivity, IV T-cells immediate maculopapular rashes Othe Multiple Variable Multiple r 69  Beta-lactams Hypersensitivity Does Cross-reactivity Exist Between Them? Degree of Cross-Reactivity PCN cephalosporins –