Common antibiotic พญ. อนงนาฏ ชนิ ะผา หนว่ ยโรคตดิ เชอื้ กลมุ่ งานอายรุ ศาสตร ์ โรงพยาบาลราชวถิ ี Outlines Antimicrobial agents Empirical treatment Antibiotic preoperative prophylaxis Endocarditis prophylaxis Sites of Action of Antimicrobial Agents in Clinical Use 1 Beta-Lactams Chemistry β-lactam ring + side chain β-lactam ring antibacterial activity Side chain antibacterial spectrum and pharmacologic properties Mechanisms of Action Inhibition of bacterial cell wall synthesis Attach to PBP on inner surface of bacterial cell membrane Bactericidal Outlines Penicillins Beta-lactam/beta-lactamase inhibitors Cephalosporins Carbapenems Monobactam Penicillins Natural penicillins Penicillinase-resistant penicillin Aminopenicillins Carboxypenicillins Ureidopenicillins Penicillin Penicillin G (IV) Penicillin V (PO) • Gram-positive cocci-most - except MRSA, penicillinase staph, penicillin-resistant S.pneumoniae - bacteriostatic against enterococci • Gram-positive rods – most - includes L.monocytogenes • Gram-negative cocci - except penicillinase N.gonorrhoeae • Anaerobes – most - except Bacteroides • Spirochetes ยาฉีด Pen G และ ยากิน Pen V - รักษาโรคติดเชื้อทางเดินหายใจส่วนบน (URI) - ปอดอักเสบ (pneumonia) - เยอื่ หุ้มสมองอกั เสบ(meningitis) - ป้องกันการเกิดโรคหัวใจรูห์มาติคจากเชื้อ Streptococci (rheumatic fever from group A Strep., Strep. pneumo.) Antistaphylococcal Penicillins Methicillin (IV) Cloxacillin (PO) Nafcillin (IV) Dicloxacillin (PO) Oxacillin (IV, PO) • stable to staphylococcal penicillinase • less intrinsic activity than penicillin G Cloxacillin - ตดิ เชื้อแบคทเี รียกล่มุ (Staph. aureus, Staph. epidermidis) Aminopenicillins Ampicillin (IV, PO) Amoxicillin (PO) • Amino side chains enhances diffusion through porin channels of GNB • No enhanced stability to -lactamases • Added activity against : - Escherichia coli - Proteus mirabilis - Haemophilus influenzae - Salmonella spp., Shigella spp. Ampicillin and amoxycillin - คอหอยอักเสบ(pharyngitis) - หูอกั เสบ(otitismedia) - ติดเชื้อทางเดินปัสสาวะ (Urinary tract infection) - กระเพาะอาหารและ/หรือลาไส้อักเสบ (gastroenteritis) จากStreptococci, H.influenzae, Proteus, E.coli, Salmonella, Shigella) Carboxypenicillins Carbenicillin and ticarcillin (IV, PO) • Activity against P.aeruginosa, Proteus. • Inactive against S.aureus, E.faecalis, L. monocytogenes • Beta-lactamase sensitive. Ureido Penicillins Mezlocillin (IV) Piperacillin (IV) • More active than carboxypenicillins against Klebsiella, enterococci, Bacteroides • Piperacillin most active against P. aeruginosa Outlines Penicillins Beta-lactam/beta-lactamase inhibitors Cephalosporins Carbapenems Monobactam Beta-lactam/ betalactamase inhibitors Clavulanate, Sulbactam, Tazobactam Little intrinsic antibacterial activity Indication:Upper & lower resp tract, GUT, skin & soft tissue infections & other infections eg osteomyelitis, septicemia, peritonitis. Rational for Beta-Lactam / Beta- Lactamase Inhibitor Combination Beta-Lactamase Enzyme Beta-Lactamase Inhibitor Bacteria Beta-Lactam Sites of Action of Antimicrobial Agents in Clinical Use 2 Outlines Penicillins Beta-lactam/beta-lactamase inhibitors Cephalosporins Carbapenems Monobactam Cephalosporins - First Generation Cefazolin (IV) Cephalexin (PO) • Gram-positive cocci • Gram-negative bacilli - except enterococci, - E.coli, P.mirabilis, MRSA, PRSP Klebsiella • Gram-positive bacilli - poor against - except Listeria H. influenzae • Gram-negative cocci • Anaerobes - except Neisseria - most except Bacteroides Cephalosporins - Second Generation Cefuroxime (IV,PO) Cefaclor (PO) Cefamandole (IV) Cefprozil (PO) Loracarbef (PO) • Increased activity against H.influenzae and M.catarrhalis Cephalosporins - Second Generation (Cephamycins) Cefoxitin (IV) Cefotetan (IV) • Increased activity against Bacteroides - 15% resistance in B.fragilis Cephalosporins - Third Generation Cefotaxime (IV) Cefixime (PO) Ceftriaxone (IV) Ceftibuten (PO) Ceftizoxime (IV) Cefpodoxime (PO) • Highly active against Enterobacteriaceae, Neisseria, H. influenzae, streptococci • Decreased activity against S. aureus (MSSA) Cephalosporins – Third Generation (Anti-Pseudomonal) Ceftazidime (IV) Cefoperazone (IV) • Highly active against Enterobacteriaceae, Neisseria spp., and H. influenzae • Most active against P. aeruginosa • Decreased activity against Gram-positive bacteria Cephalosporins – Fourth Generation Cefepime (IV) Cefpirome (IV) • Increased porin penetration • Active against P. aeruginosa • Increased stability to ESBLs, chromosomal cephalosporinases (AmpC) Anti-Bacterial Spectrum of Cephalosporins Bacteria Ceph.1 Ceph.2 Ceph.3a Ceph.3b Ceph.4 Streptococci, Staphylococci 4+ 2+/3+ 3+ 0 /1+ 3+ Pen.–Resist. S.pneumoniae 0 0 3+ 0 3+/4+ MRSA 0 0 0 0 0 Enterococcus spp. 0 0 0 0 0 Enterobacteriaceae Community-Acquired 2+/4+ 3+/4+ 4+ 4+ 4+ Hospital-Acquired 0 /1+ 1+/2+ 3+/4+ 2+/3+ 4+ P. aeruginosa 0 0 0 4+ 3+/4+ B. fragilis 0 0* 0 0 0 Ceph.3a = Cefotaxime, Ceftriaxone Ceph.3b = Ceftazidime * Cefoxitin Outlines Penicillins Beta-lactam/beta-lactamase inhibitors Cephalosporins Carbapenems Monobactam Carbapenems Imipenem(+cilastatin) (IV), Meropenem(IV) Ertapenam (IV), Doripenam (IV) • Broadest spectrum – Gram-positives, Gram-negatives, anaerobes • Stable to all -lactamases except carbapenemases Organisms Resistant to Imipenem and Meropenem • Stenotrophomonas maltophilia • Burkholderia cepacia • Enterococcus faecium • MRSA • Diphtheroids Meropenem vs. Imipenem • Similar activity against streptococci • Less active against staphylococci • More active against Gram-negative bacteria • Stable to human renal dehydropeptidase • Reduced neurotoxicity • Approved for therapy of meningitis Ertapenem • Narrower spectrum - Enterobacteriaceae - Anaerobes - less potent against Gram-positive cocci - poor activity against: • P.aeruginosa, Acinetobacter spp. • Once daily dosing • Not approved for therapy of meningitis -Lactams Adverse Effects • IgE-mediated reactions (immediate of accelerated) - Anaphylaxis • 4-15 per 100,000 courses • Deaths : 1 per 32,000-100,000 - Angioedema, urticaria -Lactams Adverse Effects • Rashes + fever - Maculopapular 2-3% • more common with ampicillin, amoxicillin 5-9% - Stevens-Johnson and related syndrome • absolute contraindication to rechallenge with -Lactams -Lactams Adverse Effects • Cross-reactivity between penicillins and other -Lactams - Less risk with 2nd and 3rd generation cephalosporins than with 1st generation cephalosporins • Carbapenem cross-reactivity -LactamsAdverse Effects • NMTT side chain - blocks enzyme vitamin Kepoxide reductase (causing hypothrombinemia) - alcohol intolerance - disulfiram reactions • Neurologic - Seizures, myoclonus (penicillins, imipenem) • Intestinal - Diarrhea (amoxicillin-clavulanate) - C.difficile-associated diarrhea (ampicillin) Sites of Action of Antimicrobial Agents in Clinical Use 1 VANCOMYCIN first glycopeptide antibiotic bactericidal (except against enterococci) Inhibits stage of peptidoglycan synthesis at site earlier than site of action of b-lactams VANCOMYCIN Constant activity against all common gram- positive bacteria - penicillin-resistant staphylococci - Staphylococci, Streptococci, Enterococci, Corynebacteria, Bacillus, Listeria, anaerobic cocci, Actinomyces, Clostridium Pharmacodynamic Total trough serum vancomycin concentrations of 15–20 mg/L are recommended in S. aureus of bacteremia endocarditis osteomyelitis meningitis hospital acquired pneumonia Monitoring of trough serum vancomycin concentrations to reduce nephrotoxicity is best Appropriate use of Vancomycin Beta-lactam-resistant GP pathogens GP infections with serious beta-lactam allergies Antibiotic-associated colitis Combination of vancomycin and gentamicin is synergistic against S. aureus and enterococci Sites of Action of Antimicrobial Agents in Clinical Use 3 Quinolones Rapidly inhibit bacterial DNA synthesis bactericidal Inhibit the enzymatic activities of two members of the topoisomerase class of enzymes: DNA gyrase (topoisomerase II) and topoisomerase IV Generation Drug Names Spectrum nalidixic acid Gram- but not 1st cinoxacin Pseudomonas species norfloxacin Gram- (including ciprofloxacin Pseudomonas species), 2nd enoxacin some Gram+ (S. aureus) and some atypicals ofloxacin levofloxacin Same as 2nd generation sparfloxacin with extended Gram+ and 3rd atypical coverage moxifloxacin Same as 3rd generation Gemifloxacin with broad anaerobic 4th *Gatifloxacin coverage *trovafloxacin *withdrawn from the market in 1999 Fluoroquinolones: 1. โรคติดเชื้อทางเดินปัสสาวะ 2. โรคติดต่อทางเพศสัมพันธ์ 3. ติดเชื้อทางเดินหายใจส่วนล่าง 4. ท้องเสียจากการติดเชื้อแบคทีเรีย 5. ตดิ เชื้อทผี่ วิ หนัง กระดูกและข้อ Metronidazole Mechanism of action: • Activated via single reduction step by bacteria forms radicals reacts with nucleic acid cell death Spectrum of activity: • Anaerobic bacteria • Microaerophilic bacteria (H. pylori) • Protozoa Sites of Action of Antimicrobial Agents in Clinical Use 4 Co-trimoxazole Trimethoprim+ sulfamethoxazole Sulfonamides: sulfisoxazole, sulphafurazole, sulfamethoxazole, sulfadiazine, sulfamethizole, sulfadimidine, sulfacarbamide, sulfadoxine, sulfasalazine Trimethoprim: diaminopyrimidine Bacteriostatic MECHANISM OF ACTION Para-aminobenzoic acid (PABA) Sulfonamides + Pteridine + Glutamic acid + Folic acid synthetase Trimethoprim Dihydrofolic acid + Pyrimethamine Dihydrofolic acid reductase Tetrahydrofolic acid Purines and pyrimidines Inhibition = Nucleic acids Spectrum Generally susceptible species (>90% susceptible) S.pyogenes S.saprophyticus