Antibacterial Agents PDF

OUTLINE Mechanisms of Introduction...

OUTLINE Mechanisms of Introduction antibiotic resistance General principle of How to deal with antibiotic treatment MDR bacteria 3000370 Principle of Pharmacology Classification of Exercise ANTIBACTERIAL ผศ. ดร. นพ.นพดล วัชระชัยสุรพล BSc (Pharm), MD, PhD, PED ID Specialist antibiotics AGENTS Department of Pharmacology, Faculty of Medicine, C H U L A LO N G KO R N U N I V E R S I T Y Suggested Reading ยา กลุม ่ ไหน ทีแ พทย์ส งจ่ ั าย https://library.md.chula.ac.th/ บ่อยทีสุด !  ผู้ชาย 20 ป ไข้ 39 °C เจ็บคอมาก ผู้ชาย 20 ป ไข้ 39 °C เจ็บคอมาก ยาปฏิช วี นะ ไอ คัดจมูก เสียงแหบ ไม่ไอ ไม่มีนํามูก ไม่คัดจมูก ปวดเมือยตามตัว ต่อมนําเหลืองทีคอโต กดเจ็บ ต้องได้รับยาปฏิชีวนะ? ต้องได้รับยาปฏิชีวนะ? 11-13% ประวัติเพิ มเติม : 3 วันก่อน ไปทัศนศึกษาทีทองหล่อ เพื อนคน ซ้ายไลน์มาบอกว่าเปนไข้หวัดใหญ่ คนขวาบอกว่า COVID-19 ตรวจร่างกาย : อ้าปากดูพบจุดหนองทีต่อมทอนซิล ของยาทีสังใช้ในแผนกผู้ปวยนอก ATK+ 30-50% เปนการสังใช้ที ไม่เ หมาะสม Lancet Infect Dis. 2021 Jun;21(6):847-857. JAMA. 2016 May 3;315(17):1864-73. Multidrug-resistant organisms WHO Bacterial Priority Pathogens List, 2024 update (MDROs) following antibiotic use Critical group High group Medium group are driven by Acinetobacter baumannii Salmonella Typhi Haemophilus influenzae (carbapenem-resistant) (FQ-resistant) (ampicillin-resistant) Enterobacterales Non-typhoidal Salmonella Group A Streptococci Overuse or misuse (carbapenem-resistant) (FQ-resistant) (macrolide-resistant) Enterobacterales Shigella spp. Group B Streptococci In both humans and (3GC-resistant) (FQ-resistant) (penicillin-resistant) Neisseria gonorrhoeae Streptococcus pneumoniae animals Mycobacterium tuberculosis (3GC, and/or FQ-resistant) (macrolide-susceptible) (rifampicin-resistant) Pseudomonas aeruginosa For instance, (carbapenem-resistant) gram mcr-1 gene (colistin-resistant) was found in Enterococcus faecium PIG  PORK  PATIENTS 3GC, 3rd generation cephalosporins; (vancomycin-resistant) Staphylococcus aureus FQ, fluoroquinolones. Ho CS, et al. Lancet Microbe. 2025. (methicillin-resistant) World Health Organization. 2024. Goodman & Gilman's the pharmacological basis of therapeutics. 14th Ed. 2022. เ ้ อ อยา เ ้อ = ชื ชื ดื้ Definitions The first antibiotic discovery Professor Alexander Fleming destroying or inhibiting the growth of microorganisms returned from his holiday and Antimicrobial and especially pathogenic microorganisms noticed something unusual on a an antibacterial substance that is isolated from petri dish. ↓⑦ Antibiotic cultures of certain microorganisms (such as fungi) or is of semi-synthetic or synthetic origin Antibacterial directed or effective against bacteria The mold had secreted something that inhibited bacterial growth Merriam-Webster dictionary OUTLINE Stages of antimicrobial therapy Mechanisms of Introduction antibiotic resistance General principle of How to deal with antibiotic treatment MDR bacteria Classification of Exercise antibiotics  Empiric vs Definitive treatment De-escalation Empiric treatment Definitive treatment When the initial empiric regimen is broader in spectrum than the definitive one. Advantages De-escalate side effet Cost / side efft cust- Amoxicillin/clavulanate Amoxicillin Meropenem Ceftazidime Vancomycin Dicloxacillin 0 อยา าไ ่ Goodman & Gilman's the pharmacological basis of therapeutics. 14th Ed. 2022. Antibiotics: WHICH ONE? The RELATIONSHIP between ANTIBIOTICS and BACTERIA ORGAN – Site of infection (clinical syndromes) It’s COMPLICATED 3 Os – Host factors Age Immune status Kidney & liver function 3 Ds 896 etc. POKEMON https://www.freepik.com/ ม่ ด้ คื Antibiotics: WHICH ONE? Carbapenem-resistant E. coli, KP ORGANISM – Susceptibility I resistance – Epidemiological data % Resistance Carbapenem- E. coli resistant E. coli ESBL-producing E. coli Antibiotics: WHICH ONE? เชือดือยาแต่อาการดีขึน à¾ÔèÁÂÒ´Õ¡Ç‹Ò ÅÑÅÅÑÅÅÑéÅÅÒ OPTIONS – Drug ต้องเปลียนยา? – Dosing – Duration A B C D เชือไม่ดือยาแต่ไม่ดีขน ึ ต้องเปลียนยา? à´ÕëÂÇÇÇ ä¢ŒÅ§áÅŒÇ äÁ‹ãª‹ËÃÍ  Factors influencing discrepancies between in vitro and in vivo in vitro and in vivo, are they similar? results Host factors Microbe factors Site of infection Inoculum effect Pharmacogenetics Heteroresistance Comorbid conditions Biofilm formation เ ่อใฟ biofi Inducible resistance ระ บย Severity of resistance Severity of resistance Pharmacokinetics Absorption Distribution Antimicrobial Escherichia coli Drug-Drug interaction Protein binding susceptibility Drug-Food interaction Site of infection testing (AST) Metabolism Excretion S, I, R Escherichia coli Pharmacogenetics Kidney and liver functions Ut versus Drug-Drug interaction MIC S, susceptible; I, intermediate; R, resistant; MIC, minimum inhibitory concentration. Drug-Food interaction ชื ดั Pharmacodynamics Time-dependent antibiotics Time dependent T>MIC 40-50% of dosing intervals Plasma drug concentration Concentration dependent e.g., Beta-lactams AUC (total exposure) dependent For instance, Dosing interval is 8 hours Minimum T>MIC is …………..hours MIC Time T>MIC Dosing interval T>MIC, the duration of plasma drug concentration above the MIC. Concentration-dependent antibiotics AUC (total exposure)-dependent antibiotics Cmax/MIC ≥ 10-12 times AUC/MIC ≥ X Plasma drug concentration Plasma drug concentration e.g., Aminoglycosides e.g., Vancomycin, FQs For instance, For instance, Cpeak The MIC is 2 mg/L Vancomycin: ≥400 (MRSA) Minimum Cpeak is …………. mg/L Ciprofloxacin: ≥100 (Gram-neg) MIC MIC Time Time Post-antibiotic effect PK and PD properties of antimicrobial agents Dose and dosing interval schedule Antibiotics with TIME-DEPENDENT Antibiotics with CONC-DEPENDENT killing activity killing activity MIC Smaller dose, Shorter interval Larger dose, Longer interval Adv Drug Deliv Rev. 2014 Nov 20;77:3-11. Combination antimicrobial therapy Synergism Indication Benefit Empirical treatment, e.g., Synergism septic shock  Additive: Meropenem + Colistin Polymicrobial infection, e.g., for P. aeruginosa infection intra-abdominal infection, (1+1 = 2)  Synergistic: Penicillins + pelvic inflammatory disease Aminoglycosides for infective Drug-resistant organisms endocarditis (1+1 > 2) Bollenbach T. Curr Opin Microbiol. 2015 Oct;27:1-9. Parenteral to oral switch therapy Community- vs Hospital-acquired bacteria Other related terms: IV to PO, step-down, sequential, follow-on Community-acquired Hospital-acquired Streptococci Advantages Staphylococcus aureus (methicillin- Staphylococcus aureus (methicillin- susceptible) resistant) Switch Enterococci Enterococci (vancomycin-resistant) Haemophilus influenzae Ciprofloxacin inj. Ciprofloxacin tab. Salmonella spp. Ampicillin inj. Amoxicillin cap. Escherichia coli Escherichia coli (multidrug-resistant) Vancomycin inj. Clindamycin cap. Pseudomonas aeruginosa Acinetobacter baumannii Goodman & Gilman's the pharmacological basis of therapeutics. 14th Ed. 2022. 3000370 Main bacterial target sites of antibiotics is just the beginning 3000373 Integumentary system 3000376 Respiratory systems II 3000380 Alimentary system II 3000381 Urinary systems II 3000383 Reproductive system II 3000386 Clinical immunology and infections in immunocompromised host 3010346 Rational Antimicrobial Use in Pediatrics (Student-Selected Components) BACTERIAL BACTERIAL https://www.freepik.com/ CELL WALL SYNTHESIS PROTEIN SYNTHESIS  BACTERIAL Steps: CELL WALL SYNTHESIS 1. Precursor Formation: NAG and NAM form the basic building blocks. 2. Peptide Chain Assembly: Peptide chains are synthesized and attached to NAM. 3. Crosslinking: Adjacent chains are crosslinked by transpeptidation. Involving enzymatic activities: Transpeptidase: Catalyze crosslinking of peptide chains. Glucosyltransferase: Assist in the polymerization of NAG and NAM. Nature Reviews Microbiology.2013;11: 601–14. BACTERIAL PROTEIN SYNTHESIS OUTLINE 30S Mechanisms of Introduction antibiotic resistance General principle of How to deal with antibiotic treatment MDR bacteria A, aminoacyl site; P, peptidyl site; E P A E, exit site. Classification of Exercise antibiotics Modified from: https://opentextbc.ca/microbiologyopenstax/chapter/protein-synthesis-translation/  Classification of antibiotics Beta-lactams Antibiotics Penicillins Cephalosporins Cell envelop Protein synthesis DNA disruptors Others Carbapenems disruptors inhibitors Monobactams Otrpoisomerase & Beta-lactams Macrolides Quinolones Aminoglycosides ↑& 505 folsa Beta-lactam/ syh Glycopeptides Lincosamides Sulfonamides =- CO- thi MUXUIUI Polymyxins · Beta-lactamase #vancomycin &-ala-&-dld target cellmemb Fosfomycin Oxazolidinones Nitroimidazoles inhibitors (BL/BIs) ท ลา ย นธะ @ L reactive spedes Tetracycli - &precursor Phenicols ⑦ https://tmedweb.tulane.edu/pharmwiki/doku.php/betalactam_pharm = Goodman & Gilman's: The Pharmacological Basis of Therapeutics, 14th ed. cabapend m + Holistin Beta-lactams: Mechanism of action Penicillins Beta-lactams, structural analogs of D-Ala-D-Ala Covalently bind to the active ยาง-lactam (โครง สรัางะcell wal site of penicillin-binding จะไป บ2n2 :ของเช proteins (PBPs), inhibiting the transpeptidation reaction Bactericidal effect Time-dependent killing activity จั ำ พั Penicillins: Classification Natural penicillins Parenteral route: Penicillin G, Narrow-spectrum Extended-spectrum Benzathine Penicillin G, Natural penicillins Penicillinase- resistant penicillins Amino-penicillins Anti-pseudomonal penicillins Procaine Penicillin G (usually dosing as “unit”) Penicillin V Dicloxacillin Ampicillin Piperacillin Oral route: Penicillin V Penicillin G Cloxacillin Amoxicillin (usually dosing as “mg”) Oxacillin Methicillin Unit and formulations – 1 mg of penicillin sodium represents 1667 units of Anti-staph penicillin Natural penicillins: Major spectrum Examples of clinical use Gram-positive Gram-negative Syphilis Streptococci Infective endocarditis caused by streptococci Enterococci Neonatal sepsis (penicillin G + gentamicin) Listeria monocytogenes · Tetanus (C. tetani) Anaerobes Others Peptostreptococcus Spirochetes Cutibacterium, Actinomyces – Treponema pallidum · Clostridium spp. EXCEPT Clostridium – Leptospira interrogans (Clostridioides) difficile Twitter @IhabFathiSulima Penicillinase-resistant penicillins Penicillinase-resistant penicillins: Major spectrum Parenteral route: Cloxacillin, (Oxacillin) Gram-positive Gram-negative Oral route: Dicloxacillin, Cloxacillin Methicillin-susceptible Methicillin Staphylococcus aureus ด (MSSA) gabsorption Streptococci Anaerobes Others Examples of clinical use Aminopenicillins Skin and soft tissue infections Parenteral route: Ampicillin – Cellulitis (group A streptococci, MSSA) Oral route: Amoxicillin # – Erysipelas (group A streptococci) – Abscess US CDC Aminopenicillins: Major spectrum Examples of clinical use Gram-positive Gram-negative Respiratory tract infections Cat/dog bite wound Streptococci Pasteurella multocida caused by susceptible Urinary tract infection (UTI) Enterococci H. influenzae (50%) bacteria Listeria monocytogenes Anaerobes Others http://www.ensg.co.nz/ Similar to penicillin ผู้ชาย 20 ป ไข้ 39 °C เจ็บคอมาก ผู้ชาย 20 ป ไข้ 39 °C เจ็บคอมาก ไอ คัดจมูก เสียงแหบ ไม่ไอ ไม่มีนํามูก ไม่คัดจมูก ปวดเมือยตามตัว ต่อมนําเหลืองทีคอโต กดเจ็บ ต้องได้รับยาปฏิชีวนะ? ต้องได้รับยาปฏิชีวนะ? ประวัติเพิ มเติม : 3 วันก่อน ไปทัศนศึกษาทีทองหล่อ เพื อนคน ตรวจร่างกาย : อ้าปากดูพบจุดหนองทีต่อมทอนซิล ซ้ายไลน์มาบอกว่าเปนไข้หวัดใหญ่ คนขวาบอกว่า COVID-19 ATK+ Clin Infect Dis. 2012 Nov 15;55(10):e86-102.  Anti-Pseudomonal penicillins: Major spectrum Examples of clinical use Parenteral route: Piperacillin (in combination with tazobactam) Serious Gram-negative infections Gram-positive Gram-negative – Nosocomial (hospital-acquired) infections – Empirical antibiotics in immunocompromised hosts, e.g., febrile Similar to ampicillin Most GN, including neutropenia cancer – Enterobacterales MSSA (Pip/Tazo) – Pseudomonas aeruginosa – Acinetobacter spp. imi ไ ตา Gram-negative + ++ +++ ++++ +++ P. aeruginosa - - - ++++ - Compared to penicillins, carbapenems are not active against A. baumannii -- - - +++ - enterococci EXCEPT for imipenem prammaries Anaerobes - +++ - +++ - (not C. difficile) Cefoxitin Cefepime http://www.mdpi.com/1422-0067/16/5/9654/htm ที จั ร้ ร้ มี ลี่ ม่  Carbapenems: Major spectrum Examples of clinical use Gram-positive Gram-negative Meropenem, Imipenem, Ertapenem Most GP Most GN, including Doripenem – Intra-abdominal and pelvic – Serious, hospital-acquired infections (excellent activity EXCEPT Enterococci – MDR-GN – P. aeruginosa infection against Gram-positive – Acinetobacter spp. – MDR, e.g., extended-spectrum organisms, ESBL-producing beta-lactamase (ESBL) Enterobacterales, and Anaerobes producing bacteria anaerobes) Ertapenem Most anaerobes not active against EXCEPT C. difficile – P. aeruginosa – Acinetobacter spp. Beta-lactamase inhibitors (BI) bac + &flactamase ่ายา & -19CHH +G B- 19CHUMAS Docquier JD, Mangani S. Drug Resist Updat. 2018;36:13-29. Bush K. Antimicrob Agents Chemother. 2018;62:e01076-18. ฆ่ Beta-lactamase classifications and substrates Beta-lactamases Ambler class: Bush–Jacoby–Medeiros Beta-lactams substrates* Examples catalytic site (spectrum) A: serine (depending on group: catalytic site (spectrum) 2a: serine (penicillinases) Penicillins Penicillinases of Gram- Narrow-spectrum subgroups) positives – Penicillinases of Gram-positives 2b: serine (penicillinases) Penicillins, first-generation cephalosporins TEM-1, TEM-2, SHV-1 2be: serine (ESBLs) Penicillins, cephalosporins (except cefoxitin and SHV-2, TEM-10, CTX-M, GES-1 Extended-spectrum ceftolozane), aztreonam – ESBL 2br: serine (inhibitor-resistant) Penicillins TEM-30, SHV-72 2c: serine (penicillinases) Penicillins PSE (CARB) – AmpC 2f: serine (carbapenemases) Penicillins, cephalosporins, carbapenems, aztreonam KPC, SME, NMC-A, GES-2 Carbapenemases gen B: metallo (carbapenemases) 3: metallo (carbapenemases) Beta-lactams, except aztreonam IMP, VIM, NDM – Serine group (KPC, OXA-48-like) C: serine (cephalosporinases) 1: serine (cephalosporinases) Penicillins, cephalosporins (except cefepime and Chromosomal AmpC, CMY, activ>– Metallo-beta-lactamase (IMP, VIM, NDM) ceftolozane), aztreonam ACT-1, DHA D: serine (oxacillinases) 2d: serine (oxacillinases) Penicillins, first- and second-generation OXA-1, OXA-10, cephalosporins and aztreonam cabapenem- penicilin Penicillins, cephalosporins, carbapenems and OXA-23, OXA-48 aztreonam *not include cefiderocol, a siderophore cephalosporin that is resistant to hydrolysis by beta-lactamases. Bush K, et al. Nat Rev Microbiol. 2019. Substrates of beta-lactamases BI: Oxapenam and penam sulfones Clavulanate, tazobactam and sulbactam Beta-lactamases Beta-lactam antibiotics Better inhibit class A beta-lactamases than C and D ↳- " Narrow-spectrum Penicillins Cephalosporins Carbapenems No or minimal bacterial killing activity – EXCEPT Sulbactam (active against A. baumannii) I ESBL Penicillins Cephalosporins Carbapenems (except ceftolozane) AmpC Penicillins Cephalosporins Carbapenems (except cefepime) Carbapenemases Penicillins Cephalosporins Carbapenems Docquier JD, Mangani S. Drug Resist Updat. 2018;36:13-29. BI: Boronic acids BI: Diazabicyclo-octanones (DABCO) Vaborbactam Avibactam – Serine-beta-lactamases including – Serine-beta-lactamases including Carbapenemases: Carbapenemases –KPC –KPC, OXA-48 Vabo Docquier JD, Mangani S. Drug Resist Updat. 2018;36:13-29. Docquier JD, Mangani S. Drug Resist Updat. 2018;36:13-29. BL/BI Spectrum of commonly used BL/BI Beta-lactam/Beta-lactamase inhibitors Enterococci Gram-positive Gram- Anaerobes A. baumannii* P. aeruginosa* Broader spectrum negative (not C. difficile) Ax or Ap Not for MSSA – Amoxicillin / Clavulanate (AUGMENTIN) Ax/Cla – Ampicillin / Sulbactam (UNASYN) Ap/Sul Sul – Piperacillin / Tazobactam (TAZOCIN) Pip/Tazo – Cefoperazone / Sulbactam (SULPERAZON) Cefz/Sul – Ceftazidime / Avibactam (ZAVICEFTA) – Ceftolozane / Tazobactam (ZERBAXA) Ax, amoxicillin; Ap, ampicillin; Pip, piperacillin; Cefz, Cefoperazone; Cla, clavulanate; Sul, sulbactam; Tazo, tazobactam. *non-MDR strains  อ Inhibitory spectrum of beta-lactamase inhibitors Beta-lactams: ADR = Beta-lactams Beta-lactamase Spectrum of inhibition on clinically important beta-lactamases Side effects Drug hypersensitivities inhibitors ESBL AmpC Carbapenemases – GI disturbance – Immediate type, e.g., urticaria, on KPC OXA-48 MBL Amoxicillin Clavulanic acid O X X X s X – CNS, e.g., seizure anaphylaxis Ampicillin Sulbactam O X X X X – Hematologic, e.g., – Delayed type, e.g., drug rash Piperacillin Tazobactam O X X X X thrombocytopenia Ceftolozane Tazobactam O X X X X with eosinophilia and systemic Ceftazidime Avibactam O O O O X – Hepatotoxicity, esp., clavulanic symptoms (DRESS) Imipenem Relebactam O O O X X acid in elderly Meropenem Vaborbactam O O O X X ESBL, extended-spectrum beta-lactamases; MBL, metallo-beta-lactamases. O inhibitory effect; X no inhibitory effect. อน ก inhibi+ห เ ่อชนะ !I Beta-lactam cross-reactivity 6-25% in prevalence Rates of cross-reactivity of penicillins – Cephalosporins < 5% 90% can be delabeled – Carbapenems < 1% by assessment and/or allergy testing enicillin Disproved penicillin allergy labeling has negative impacts on the Allergy health care system. It is associated with the acquisition of MRSA, increased hospital length of stay and drug costs, and excess patient mortality. Ann Allergy Asthma Immunol. 2023 May;130(5):554-564. Clin Infect Dis. 2021 Aug 2;73(3):487-496. doi: 10.1093/cid/ciaa653. J Pharm Pract. 2014;27:530-44. อ่ น่ ก่ ถู  Penicillins Cephalosporins http://www.clevelandclinicmeded.com/ Patrick DM et al. BCMJ, Vol. 61, No. 9, November, 2019, 350-1. act cell-wa Glycopeptides Parenteral route: Vancomycin, teicoplanin Oral route: Vancomycin (poorly absorbed) local infection in Comparison of R1 and R2 structural similarities between b-lactam drugs. Drugs that have identical R1 or R2 structures are listed as R1 (red cell) or R2 (gold cell). If only the ring or branch chain moiety of the R1 structure is identical, it is listed as R1’ or R1’’, respectively. Drugs that have similar R1 or R2 structures are listed as r1 or r2. If only the ring or branch chain moiety of the R1 structure is similar, it is listed as r1’ or r1’’, respectively. Blank cells imply no R1 or R2 structural similarities. Zagursky RJ, Pichichero ME. J Allergy Clin Immunol Pract. 2018;6:72-81.e1 ี่ ที Glycopeptides: Mechanism of action Glycopeptides: Major spectrum Inhibit cell wall synthesis Gram-positive Gram-negative by Broad spectrum, including – Binding to the terminal D- – MRSA Ala-D-Ala end, then – PRSP preventing transpeptidation – Ampicillin-resistant Enterococci – Inhibiting neighboring transglycosylase activity by Anaerobes Others steric hindrance Gram-positive anaerobes, including C. difficile http://tmedweb.tulane.edu/pharmwiki/doku.php/antibiotic_pharmacology Examples of clinical use Vancomycin # Skin/soft tissue and Antibiotic-associated colitis increases mortality rates bone/joint infections (AAC) caused by C. difficile when used for MSSA Catheter-related bloodstream (oral administration) The hazard of mortality decreased infections for patients who received cefazolin – Methicillin-resistant or antistaphylococcal penicillins staphylococci compared with vancomycin CNS infections (HR, 0.57; 95% CI, 0.46-0.71) – Drug-resistant S. pneumoniae – VP shunt infections McDanel JS, et al. Clin Infect Dis. 2015;61:361-7.  เ ยว บ cell wall Glycopeptides: ADR Fosfomycin Vancomycin infusion reaction Parenteral and oral routes (AKA, vancomycin flushing Mechanism of action syndrome), the extreme block # recep – Inhibit bacterial cellนwall flushing synthesis by inhibiting (previously known as Red man syndrome) enolpyruvate transferase (MurA) Nephrotoxicity and blocking the addition of Ototoxicity phosphoenolpyruvate to UDP- N-acetylglucosamine http://journal.frontiersin.org/article/10.3389/fpubh.2014.00217/full Fosfomycin Polymyxins Gram-positive Gram-negative Parenteral route MSSA, MRSA, MRSE Enterobacterales – Polymyxin E (Colistin) – Polymyxin B E. faecalis, E. faecium P. aeruginosa Mechanism of action – Act as cationic detergents Examples for clinical Interact strongly with phospholipids displacing cations Clinical use ADR that form bridges between LPS Skin and soft tissue infections GI disturbance molecules, and then disrupt the UTI structure of cell membranes Rare: hepatotoxicity, aplastic MDR-GNB treatment (in anemia combinations) eLife. 2021; 10: e65836. ยา น 1doseจ ต้ กั กี่ กิ Colistin Macrolides +> ยา Gram-negative 14-membered ring Carbapenem-resistant GN – Erythromycin (O) – Enterobacterales – Roxithromycin (O) – P. aeruginosa – Clarithromycin (O) – A. baumannii 15-membered ring Clinical use – Azithromycin (P, O) MDR-GNB infections (combination or 16-membered ring monotherapy) – Midecamycin (O) ADR Nephrotoxicity Neurotoxicity P, Parenteral route; O, Oral route. Song X, Zhou T, et al. Molecules. 2018;23. Macrolides: Mechanism of action Macrolides: Major spectrum Inhibit protein synthesis by Gram-positive Gram-negative binding to 50S ribosomal subunits ~ Streptococci MSSA H. influenzae M. catarrhalis Bordetella pertussis Bacteriostatic effect (may be Corynebacterium diphtheriae Campylobacter spp. bactericidal in high Helicobacter pylori (Clarithromycin) concentrations) Time-dependent killing Anaerobes Others activity Atypical pathogens – Chlamydia trachomatis, Chlamydophila pneumoniae, Mycoplasma pneumoniae – Rickettsia species Nontuberculous Mycobacteria (NTM) กิ Summary of macrolides spectrum จับตาโรคและภัยสุขภาพ Erythromycin Azithromycin Clarithromycin โรคปอดอักเสบจากเชือ Roxithromycin Mycoplasma pneumoniae Midecamycin December 2024 ↳ Streptococci MSSA M. catarrhalis H. influenzae คร. เผยผลสอบสวนโรค Atypical bacteria "เด็กนร.ปวยไอกรน" กว่า NTM 20 ราย ชีอาการไม่รุนแรง H. pylori ไม่แนะนําปดโรงเรียน November 2024 Examples of clinical use Macrolides: ADR / DI / Precaution A penicillin substitute in NTM (in combination with the ADR Drug interaction penicillin-allergic individuals other ABX) GI upset: nausea, vomiting, CYP 3A4 inhibitors with infections caused by H. pylori treatment (as triple diarrhea increase plasma drug conc. of staphylococci and therapy) Cardiac arrhythmia: prolonged QT CYP 3A4 substrates, e.g., interval, Torsades de pointes Theophylline, Digoxin, Warfarin streptococci Atypical pneumonia, e.g., Mycoplasma pneumonia CYP 3A4 substrates CYP 3A4 Inactive metabolites CYP 3A4 CYP 3A4 Inactive substrates metabolites Lincosamides Lincosamides: Major spectrum Parenteral route: Lincomycin, Gram-positive Gram-negative Clindamycin MSSA Oral route: Clindamycin Community-associated MRSA Mechanism of action (CA-MRSA) – Inhibit protein synthesis by Streptococci binding to 50S ribosomal Lincosamides subunits Anaerobes Others – Static or cidal effect depends on Most anaerobes EXCEPT C. Clindamycin plus primaquine concentrations difficile Pneumocystis jirovecii pneumonia – Time-dependent killing activity Drug-resistant strains are Clindamycin (in combinations) Malaria increasing Examples of clinical use Clindamycin: ADR / DI / Precaution An alternative for penicillin- # ADR allergic patients for treating skin Dermatologic: rash, pruritus and soft tissue infections Gastrointestinal: Abdominal Lung abscess and anaerobic lung and pleural space infections pain, diarrhea, nausea In combination with anti- Antibiotic-associated colitis staphylococcal beta-lactams for (caused by C. difficile) treating toxic shock syndrome CA-MRSA infections  Oxazolidinones Linezolid: Major spectrum Linezolid (P, O) Gram-positive Gram-negative Inhibit protein synthesis by Most GP, including MDR binding to the P site of the 50S – Enterococci including VRE ribosomal subunit and – Staphylococci including MRSA, preventing formation of the VRSA initiation complex. https://pharmaxchange.info/2011/06/mechanism-of-action-of-oxazolidinones/ Anaerobes Others Gram-positive anaerobes Mycobacteria – Mycobacterium tuberculosis – NTM &pac. meniglisis ridrug อ Linezolid: Example for clinical use / ADR / DI Chloramphenicol Vancomycin-resistant Gram- ADR Mechanism Spectrum positive, e.g., VRE Common: rash, GI, headache Serious Inhibit protein synthesis by Broad spectrum: aerobes, – Prolonged use >2 weeks: binding to the 50S ribosomal anaerobes, atypical Myelosuppression – Prolonged use >8 weeks: Peripheral subunit (static effect) pathogen, spirochetes คนไ = UT neuropathy, optic neuritis, and lactic acidosis DI Clinical use ADR / DI toxic metabolite ท ลาย stemce Linezolid is a weak nonspecific Aplastic anemia (irreversible) inhibitor of monoamine oxidase Bacterial meningitis, Inhibit hepatic CYPs, then increase Rickettsial diseases that ② another drug level e.g., warfarin, failed other drugs phenytoin, protease inhibitors ี้ ข้ ำ  Aminoglycosides Aminoglycosides: Mechanism of action Parenteral route Inhibit protein synthesis by binding to 30S ribosomal subunits – Amikacin Bactericidal effect – Gentamicin Concentration-dependent killing activity – Netilmicin – Tobramycin – Kanamycin – Streptomycin Oral route – Neomycin Aminoglycosides: Major spectrum Aminoglycosides: Examples of clinical use รพ ~ยา ด +toxicit Gram-positive Gram-negative # MDR-GN nosocomial Second-line agent for treating (in combination with cell wall Most GN including infections tuberculosis (Amikacin) active agents) – MDR-GN In combination with cell wall Enterococci – A. baumannii active agent for treating gram- Streptococci – P. aeruginosa positives Staphylococci – Bacterial endocarditis Istreptstraps #@ penicillin -> Anaerobes Others – Severe Enterococcal infections aminoglycoside Mycobacteria – Mycobacterium tuberculosis – NTM ฉี  Aminoglycosides: ADR / DI / Precaution Tetracyclines ADR dripos * 2347 Parenteral route - Rวง Nephrotoxicity Neuromuscular transmission – Doxycycline - fux gr. เยอย Ototoxicity (generally blockade – Minocycline irreversible) – Use with caution in patients Oral route – Vestibular damage: vertigo, with neuromuscular disorders, – Doxycycline ataxia, and loss of balance e.g., myasthenia gravis – Minocycline – Auditory damage: tinnitus, – Tetracycline ยาทาา hearing loss (high-frequency Topical route initially) – Oxytetracycline Tetracyclines: Mechanism of action Tetracyclines: Major spectrum Inhibit protein synthesis by Gram-positive Others binding to 30S ribosomal Bacillus anthracis Mycoplasma spp. Chlamydia spp. #wal antrak subunits macroline Gram-negative ↑ Rickettsiae ซ ceptriazone ฟ :pen d, 3rdge Helicobacter pylori chatitomycin / Spirochetes (T. pallidum, L. n,(macr Vibrio spp. interrogans, Borrelia Brucella spp. burgdorferi) Yersinia pestis Plasmodium vivax malari Francisella tularensis Plasmodium falciparum ซิ สิ ฟิ ลิ  Tetracyclines: Examples of clinical use Tetracyclines: ADR / DI / Precaution Anthrax ADR ควร นห งอาห Atypical pneumonia DI 2) ↓ GI disturbances: nausea, Absorption impaired by polyvalent H. pylori GU, DU Rickettsial diseases vomiting, esophagitis Cholera Syphilis cations Bony structures and teeth Brucellosis Leptospirosis Avoid using in pregnancy and lactation (9(03 Plague women and children under 8 years old Tularemia # Lyme disease (EXCEPT Doxycycline) OK Malaria – Teeth: discoloration, and enamel dysplasia https://www.cda-adc.ca – Bone: may cause deformity or growth inhibition Photosensitivity ทาง SUNbIOCK ว Thai PBS News, December 2024. 0 ก าาง น >ทน ทา อกการ =- tetracycline modified Glycylcyclines: Major spectrum Tigecycline: Examples of clinical use Parenteral route: tigecycline Hospital-acquired Gram-negative infections (especially for carbapenem-resistant Enterobacterales, A. baumannii) Gram-positive Gram-negative Most GP including MDR-GP MDR-GN 3 – MRSA, VRSA – Carbapenem-resistant Enterobacterales (CRE) ร – VRE Clinical scenario – A. baumannii IRAB Oxacisininone – Stenotrophomonas maltophilia A stroke patient with ventilator- NOT active against P. aeruginosa associated pneumonia (VAP) A. DAU Tracheal suction grows A. baumannii Anaerobes Others & Most anaerobes (C. difficile ?) Atypical pathogens ด้ ต่ กิ ลั ขึ้ ว้  modifie Fluoroquinolones (FQs) อ งเส Fluoroquinolones: Mechanism of action Norfloxacin (O) Block bacterial DNA synthesis Bactericidal effect Ofloxacin (P,O) by inhibiting bacterial Concentration-dependent Levofloxacin (P,O) topoisomerases killing activity ใช้ว นล ะ 1 Ciprofloxacin (P,O) – Topoisomerase· II (DNA gyrase) Moxifloxacin (P,O) of Gram-negative bacteria – Topoisomerase · IV of Gram- positive bacteria Fluoroquinolones: Major spectrum Summary of fluoroquinolones spectrum Gram-positive Gram-negative * Oflox Ciproflox g Levoflox Moxiflox MSSA Enterobacterales %ไ ใใ S. pneumoniae Including PRSP Including PRSP S. pneumoniae, PRSP Campylobacter spp. Macroli P. aeruginosa (Ciprofloxacin, S. aureus MSSA (MRSA) (Levofloxacin, Moxifloxacin) / Levofloxacin) 4 oral ้ psudomon P. aeruginosa S. maltophilia (Levofloxacin) M. tuberculosis Atypical pathogens Anaerobes * Others Anaerobes Most anaerobes EXCEPT C. Atypical pathogens -not first line Mycobacteria อย difficile (Moxifloxacin) – Mycobacterium tuberculosis – NTM วั ห้ คื ม่ ที  Fluoroquinolones: Example for clinical use Fluoroquinolones: ADR / DI / Precaution Consider as an alternative ADR ·- Felt DI – Urinary tract infection gram GI: nausea, vomiting, abdominal Absorption impaired by polyvalent – Bacterial diarrhea vibric, Bacter discomfort cations ~ tetra – Pneumonia, including atypical Neurologic: headache, dizziness, + CYP 1A2 inhibitor (cipro): · -> increase pneumonia insomnia, and anxiety theophylline plasma level – Bone, joint, and soft-tissue Musculoskeletal: arthralgia, joint infections pain, tendinitis # Others=rupture of tendon &– QT interval prolongation (rare; moxi > levo, oflox > cipro) ~macroline – Dysglycemias 8 poor control 8 M ↑If Sulfonamides Co-trimoxazole: Mechanism of action Sulfamethoxazole- + Interfere with bacterial folic Trimethoprim (co-trimoxazole, acid synthesis esis Bactrim)(P, O) Sulfonamides are competitive Silver sulfadiazine (topical) inhibitors of dihydropteroate แผลไฟไห ้ อ synthase Trimethoprim prevents the reduction of dihydrofolate to tetrahydrofolate St Synergistic activity ร้ น้ ำ ม้  Co-trimoxazole: major spectrum Example for clinical use: Co-trimoxazole Gram-positive Gram-negative UTI LE. COli) Streptococci that first line Enterobacterales UTI Salmonella enteritis MSSA, CA-MRSA Burkholderia pseudomallei Melioidosis (B. อไ S. maltophilia ccarry 1gene % pseudomallei) A. baumannii ↓ Pneumocystis jiroveci Anaerobes Others pneumonia Pneumocystis jiroveci Toxoplasma gondii Toxoplasma gondii { opportunitiC meningoencephalitis Co-trimoxazole: ADR / DI / Precaution Metronidazole (Nitroimidazoles) ADR aแ บ ย ยาจับ + free bilirubin penitrate เ ขา b Metronidazole (O, P) Severe skin reaction Kernicterus in neonates (due Mechanism of action – Stevens-Johnson Syndrome Cyp# to high protein binding) – Reduction of nitroimidazoles by * ferredoxin produces nitro radicals ว (SJS)/Toxic Epidermal Hepatic necrosis which then attack the DNA of Necrolysis (TEN) parasites or anaerobes to cause a stable Hematologic disorders +กด BM loss of helical structure, strand Onnut rad. – Anemia breakage (-cidal effect) – Agranulocytosis – Thrombocytopenia – Hemolytic anemia in G6PD deficiency flono. * anaerobe &parasite ถื ม่ ดี สั  Metronidazole Anti-anaerobes: spectrum anderobe angerobe gram # gram Spectrum Peptostrepto- coccus Actinomyces Cutibacterium -> pimple Clostridium (non-C. C. difficile Bacteroides and other GNB difficile) Obligate anaerobic bacteria, Pen -lactamase ( including Bacteroides, C. difficile, and microaerophilic bacteria, e.g.,