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

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

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

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

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

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  L.monocytogenes  B.pertussis  Y.enterocolitica  Aeromonas spp.  B.pseudomallei  B.cepacia  S.maltophilia  P.carinii (jeroveci)  Nocardia spp.

Spectrum

 Varying susceptibility species  S.pneumoniae  S.aureus  Coag-Neg Staph.  Enterococcus spp.  E.coli  Enterobacter spp.  Klebsiella spp.  Salmonella spp.  Shigella spp.  Campylobacter spp.  H.influenzae  M.catarrhalis

Co-trimoxazole 1. Acute UTI (recurrent/ chronic อาจดื้อยาแล้ว) 2. Nocardia asteroides, Toxoplasma 3. Pneumocystis carrinii pneumonia prophylaxis 4. Acute otitis media, chronic bronchitis from H. influenzae, S. pneumoniae Adverse effect

 Hyperkalemia  Bone marrow suppression  Drug allergy Sites of Action of Antimicrobial Agents in Clinical Use

Tetracycline

 Broad-spectrum activity  Includes aerobic GP and GN, atypicals [Rickettsia , Treponema , Chlamydia  bacteriostatic effect

 Tetracycline  Doxycycline*  Minocycline  Tigecycline

Drug of choice: Mycoplasma, Chlamydia, Rickettsiae,Vibrio, ไชไ้ ดผ้ ลกบั G+ G-,anaerobes ในช่องทอ้ ง, Respiratory infection, Acne Adverse Effects:  Photosensitivity  Discoloration of teeth  Nausea, Vomiting, Diarrhea (esophagitis – doxycycline)  Hepatotoxicity  Candidal superinfection

Tigecycline

 First clinically-available drug in a new class of antibiotics: glycylcyclines

 Structurally similar to the tetracyclines

 Actually a derivative of minocycline

 broad spectrum activity Tigecycline

 Dosing: Loading dose of 100 mg Maintenance dose: 50 mg q12h x 5-14 d.  FDA indications: - complicated SSTIs - intraabdominal infections  Thailand – A.bau (MDR)

Aminoglycoside

 bactericidal against - aerobic gram-negative bacilli including P. aeruginosa - some gram-positive aerobic cocci  Lack activity against anaerobes Toxicity

 Nephrotoxicity proximal convoluted tubules

*Increased nephrotoxicity in - elderly, prolonged use, DM - with concurrent use of vancomycin, loop diuretics, cyclosporine, cisplatin

 Oto-vestibular toxicity

 Neuromuscular blockade Clinical implication

 Combination therapy with other antimicrobial agents for serious GNB infections  Combination with cell-wall–active antibiotics

synergistic for serious GPC (staphylococcal, enterococcal, streptococcal endocarditis  Mycobacterium

 Less common pathogens -Yersinia pestis, Brucella spp, and Francisella tularensis Sites of Action of Antimicrobial Agents in Clinical Use

Macrolides

 Bacteriostatic

 Active against gram-positive

 Weakly active against many gram-negative

 Erythromycin, Clarithromycin, Azithromycin, Roxithromycin

Macrolides

Pharmacokinetics/Pharmacodynamics

 Extensive tissue penetration esp. alveolar macrophage and epithelial lining fluid  Good for treatment the infection caused by intracellular pathogens ** choice for CAP S. pneumoniae, H. influenzae, M. cattarhalis

Macrolides

Adverse effect  Nausea & vomiting  Combination with statins lead to myopathy  A class effect of QT prolongation “torsade de pointes” Clindamycin Antibacterial activity

 Active against - Gram-positive : most streptococci, MSSA - Anaerobic gram-negative bacilli including Bacteroides spp., Fusobacterium spp. - Anaerobic gram-positive bacilli - Protozoa: Toxoplasma gondii, P. falciparum, P. jeroveci

ไช้ได้ผลกับ G+ & most anaerobes ในช่องท้อง ปอด Clindamycin Adverse effects

- Diarrhea - Pseudomembranous colitis - Nausea & vomiting - Abdominal pain or cramps - Rash, and/or itch. - High doses may cause a metallic taste - Topical may cause contact dermatitis

Sites of Action of Antimicrobial Agents in Clinical Use

Polymyxins

• Polypeptides discovered in 1947

• Spectrum of Activity Narrow spectrum Most aerobic GNB including P. aeruginosa & Acinetobacter

• Parenteral colistin dosing CrCl > 50 3.0-5.0 mg/kg/day (q12h) CrCl 10-50 2.5 mg/kg/day (q12-24h) CrCl < 10 1.5 mg/kg/day (q36h)

Aerosolized polymyxins  To improve concentrations in distal airway and reduce systemic toxicity

 Dosing 75-300 mg/day of colistin base, q 12-24h for inhalation

Intrathecal colistin administration

 penetrate poorly in CSF  Intrathecal use is safe, effective for MDR GNB infection.  Dosing ranging from 1.6-20 mg/day (q12-48h)

Adverse Effects

 Nephrotoxicity (10% - 20%) : ATN

 Neurotoxicity (7%) : Dizziness, weakness, facial paresthesia, vertigo, visual disturbances, ataxia, confusion, neuromuscular blockade which can lead to respiratory failure or apnea Adverse Effects

Polymyxins in nebulization  Induce bronchospasm  minor symptoms -cough, sore throat, chest tightness

Intrathecal polymyxins  Neurotoxicity - Meningeal irritation; most frequent 20% Sites of Action of Antimicrobial Agents in Clinical Use

Linezoild

 First of oxazolidinone antibiotic class

 The inhibition of a novel site in ribosomal protein synthesis, interfering with functional initiation complex formation

 Available for both IV and oral -> 100% oral bioavailability Linezoild: clinical application

 Nosocomial pneumonia caused by S. aureus (MSSA and MRSA) or S. pneumoniae (including MDR strains)

 Complicated skin and skin structure infection including diabetic foot infections, without concomitant osteomyelitis, caused by S. aureus (MSSA & MRSA), S. pyogenes or S. agalactiae. Toxicity & Adverse Reaction

 Reversible myelosuppression - anemia - leukopenia - pancytopenia - thrombocytopenia  Typically in prolonged used  CBC should be monitored weekly Site/Diagnosis Potential Causes Definitive Therapy Community acquired S. pneumoniae, H. Influenzae, Amoxicillin/Clarulanic â, Ceftriaxone pneumonia Mycoplasma, Chlamydia Macrolide (Clarythromycin, azithromycin)

Urinary tract infection E.Coli, Klebseilla Aminoglycoside, Amoxy/clavulanic, (Community) Ceftriaxone

Urinary tract infection E.Coli, Klebseilla, Ceftazidime, 4thceph,carbapenem (Nosocomial) Pseudomonas

Skin and soft tissue Streptococcus, Penicillin Infection Staph aureus Cloxacillin (Community) E.coli Ceftriaxone

Skin and soft tissue MRSA Vancomycin Infection Gram negative Ceftazidime,4th ceph, (Nosocomial) Cefoperazone/sulbactam

Intra abdominal / E.Coli, Klebseilla, Ceftriaxone + Metronidazole biliary tract infection Enterobactor, anaerobe Amoxy/Clavulanic â, Ampicillin/Salbactam

Neutropenia Gram negative (P. aeruginosa) Ceftazidime, cefipime, cefpirome Gram Positive (S.aureus) + aminoglycoside or ciprofloxacine

Intra-operative antimicrobial dosing

Antimicrobial Agent Timing of Redose Post-op dose

Cefazolin Q4 Hrs Q8 Hrs Cefotetan Q12 Hrs Q12 Hrs Ciprofloxacin Q12 Hrs Q12 Hrs Clindamycin Q8 Hrs Q8 Hrs Gentamicin Q8 Hrs Q8 Hrs Metronidazole Q8 Hrs Q8 Hrs Vancomycin Q12 Hrs Q12 Hrs TMP-SMX Q12 Hrs Q12 Hrs AHA endocarditis guideline 2007

Antibiotic prophylaxis is indicated for following high-risk cardiac conditions

1. Prosthetic cardiac valve

2. History of infective endocarditis

3. Congenital heart disease (CHD) (1) unrepaired cyanotic CHD (2) completely repaired congenital heart defect with prosthetic material or device, during first 6 months after procedure (3) repaired CHD with residual defects at site of a prosthetic device

4. Cardiac transplantation recipients with cardiac valvular disease

AHA endocarditis guideline 2007

Antibiotic prophylaxis is indicated for following high-risk procedure

1. All dental procedures that involve manipulation of gingival tissue or perforation of oral mucosa

2. Invasive procedure of respiratory tract that involves incision or biopsy of respiratory mucosa, such as tonsillectomy, adenoidectomy

3. Patients with existing GI or GU infection

4. Procedure involving infected skin and soft tissue infection

5. Prosthetic heart valves, prosthetic intravascular or intracardiac matherial replacement