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Principles of anti-infective therapy

1. Choice of proper anti-microbial agent

2. Anti-microbial combinations

3. Dosage and evaluation of efficacy

Choice of proper anti-microbial agent

1. Identification of infecting organism

2. Determination of anti-microbial susceptibility of infecting organism

3. Host factors:

history of previous adverse reactions to antimicrobial agents, age, genetic or metabolic abnormalities, pregnancy, renal & hepatic function, site of infection

Anti-microbial combinations

1. in-vitro results

2. Indications for clinical use:

prevention of emergence of resistant organisms, poly-microbial infections, initial therapy, decreased toxicity, synergism

3. Disadvantage of inappropriate use:

antagonism, cost, adverse effects

Dosage and evaluation of efficacy

1. Route of administration

2. Dosing regimen

3. Monitoring response of patient to anti-microbial therapy

Molecular mechanisms of antibiotic resistance in bacteria

1. Molecular genetics of antibiotic resistance

2. Mechanisms of antibiotic resistance

3. Control of antibiotic resistance

Molecular genetics of antibiotic resistance

1. Plasmids

2. Transposable genetic elements

3. DNA integration elements

Mechanisms of antibiotic resistance

1. Enzymatic inhibition

2. Decreased permeability of bacterial membrane

3. Promotion antibiotic efflux

4. Altered target sites

5. Altered of target enzymes

6. Overproduction of target

Pharmacokinetics & pharmacokinetics of anti-

infective agents

1. Pharmacokinetics (PK)

2. Pharmacokinetics (PD)

Pharmacokinetics (PK)

1. Pharmacokinetic modeling

2. Absorption

3. Distribution

4. Metabolism and bio-transformtion

5. Elimination

Pharmacokinetics (PD)

1. Antimicrobial activity 2. Methodology for study of PD effects of

anti-infective agents (1) in-vitro models / animal models / human trials (2) concentration-dependent killing agents (3) time-dependent killing agents (4) post-antibiotic effect

Introduction of antibiotics

1. Penicillins 2. Cephalosporins 3. Other ß-lactam 4. Fusidic acids 5. Aminoglycosides 6. Tetracyclines & chlora

mphenicol 7. Rifamycins 8. Metronidazole 9. macrolides, clindamyc

in, ketolides

10. Glycopeptides 11. Polymyxins 12. Oxazoidinones 13. Sulfonamides & trimethoprim 14. Quinolones 15. Antimycobacterail agents 16. Systemic antifungal agents 17. Antiviral drugs

Penicillins (PCN)

1. Mechanism of action

2. Bacterial resistance

3. Classification

4. Pharmacologic properties

5. Untoward reactions

6. Clinical use

Classification

1. Natural penicillins: PCN G, PCN V

2. Isoxazolyl penicillins (penicillinase-resistant penic

illins): methacillin, nafcillin

3. Aminopenicillin: ampicillin, amoxicillin

4. Carboxy-penicillins: carbenicillin, ticarcillin

5. Ureidopenicillins: azlocillin, mezlocillin, piperacillin

Cephalosporins

1. Classification

2. Mechanism of action

3. Spectrum of activity

4. Mechanism of resistance

5. Pharmacologic properties

6. Adverse reactions & toxicities

7. Clinical use

Classification

1. First generation: cefazolin, cephalothin, cephapirin,

cephradine

2. Second generation: cephamycin; cefamandole, cef

onicid, cefuroxime, cefmetazole, cefotetam, cefoxitin

3. Third generation: cefoperazone, cefotaxime, ceftazi

dime, ceftizoxime, ceftriaxone, moxalactam

4. Fourth generation: cefepime, cefpirome

5. Oral form: first, second, third generation

Other ß-lactam

1. Carbapenems: thienamycin, imipenem, meropenem, ertapenem

2. Monobactams: aztreonam

3. ß-lactamase inhibitors:

(1) clavulanate

(2) sulbactam

(3) tazobactam

Aminoglycosides

1. Mechanism of antimicrobial activity 2. Aminoglycoside resistance: (1) intrinsic (2) acquired: reduction entry / efflux, enzymatic modification 3. Pharmacology: administration, distribution, metabolism,

excretion 4. Toxicity: renal, ear (cochlear, vestibular), neuromuscul

ar blockade 5. Clinical use / dose given: MDD / ODD 6. Special indication: cystic fibrosis, IE, peritonitis, gonorr

hea

Penicillin

1. Nucleus: thiazolidine ring / ß-lactam ring / side chain

2. ß-lactamase from S. aureus to hydrolysis ß-lactam ring

3. Inhibit cell wall / peptidoglycan => Gm(+) vs Gm(-) 50~100 vs 1~2 molecules

4. PBP (penicillin-binding protein): trans-peptidation / carboxy-peptidation & inhibited by ß-lactam antibiotics

Bacterial resistance

Mechanism: (1) destruction by ß-lactamase

(2) failure to penetrate outer membrane

of GNB to reach PBP

(3) GNB outer membrane efflux drug

(4) binding affinity decreased to PBP

Untoward reactions

Hypersensitivity reactions: 1. Range from rash to anaphylaxis and act as ha

pten to combine with protein

2. Penicillin allergy: (1) major determinant: penicilloyl and

penicillanic acid derivative (2) minor determinant: benzyl penicillin, Na benzyl penicilloate

3. Mediated by IgE and minor determinant are major cause of anaphylactic reactions

Cephalosporin

1. 1945 discovery => 1964 cephalothin => >20 available (from cephalosporin C)

2. Broad spectrum, low toxicity, easy used, favored PK profile

3. Cephem nucleus: ß-lactam ring fued c 6-member dihyfrothiazine ring (S)

Classification

Related to microbiologic & pharmacologic differences:

1st: focus on Gm(+) 2nd: varying on Gm(+) & enhanced on GNB; ceph

amycin => against anaerobic bacteria, as B. fragilis

3rd: marked increased on GNB, but GPC decreased & ceftazidime for P. aeruginosa

4th: active against GNB (P. aeruginosa) & GPC => 3 / 4 so-called extended spectrum cephalospori

ns / ESBL or ampC

1. ß-lactamase destruction (1) staphylococci: reduced by binding affinity to BPB

decreased (2) GNB: type / amount vary and antibiotic degrade

d at periplasmic space 2. Reduce penetration of antibiotic through membrane

to PBP: through porin depend on size, shape, charge & hydrophilic

3. Increased efflux from periplasmic space: higher permeability in E. coli than P. aeruginosa (due to AcrAB efflux system)

4. Alteration PBP to reduce binding affinity: S. pneumoniae, MRSA, H. influenzae, N. gonorrhea

Mechanism of resistance

Adverse reactions and toxicities

1. Hypersensitivity reactions: most common, but less than penicillin; associated c cutaneous rash, eosinophilia, fever & infrequently c serum sickness, anaphylaxis, angioedema

2. Hematologic reaction: eosinophilia, cytopenia (WBC, pl & RBC)

3. GI tract: diarrhea, obstructive biliary toxicity (ceftriaxone)

4. Others: seizure, local phlebitis, pain IIM), superinfection or overgrowth of Candida spp. / Cl. difficle

Aminoglycosides

1. 1940 one part of As, belongs to conc-dependent bactericidal activity

2. Active for P. aeruginosa, mycobacteria, protozoan, N. gonorrhea

3. Potential of toxicity: nephro, oto-toxicity & neuro-muscular blockade

4. Resistant decreased by known mechanism, new dosage strategies, avoid risk factors, shorter course

Mechanism of resistance

1. Intrinsic:

(1) enzyme: active electron transport

chain => anaerobic bacterail to AG

(2) non-enzyme: mutations at 16S rRNA

=> M. tuberculosis (SM), M.

abscessus, M. chelonae (amikacin)

2. acquired: combined of

(1) decreased drug intake

(2) efflux pump activity

(3) enzyme modification

3. Exposure to AG can select 2 types of

drug-resistant subpopulations

(1) activattion of Mex XY efflux pump

(2) phenomen of adaptive resistance =>

clinical tx failure

4. Enzymatic modification:

(1) amino group => modified by N-acetyl-

transferase (AAC)

(2) hydroxyl group => modified by O-

nucleotidy-transferase (ANT) or O-

phospho-transferase (APH)

(3) modofied drug bind poorly to

ribosomes => high level of resistance

Toxicity

1. Other than spectinomycin, AG had the potential injury to renal PCT, damage to cochlea / vestibular apparatus & neuro-muscular blockade

2. Untoward effects (rare): hypersensitivity reactions, inflammation, phlebitis, pain while injection (IM), no irritation on cavity injection, hepatoxicity or photosensitivity

Once-daily dosing regimens

1. Total daily dosage could achieve targeted peak serum conc. for a given level of renal function

2. When renal function impaired, total daily dose may be reduced or dosage interval prolonged

Glycopeptides & lipopeptides

1. vancomycin: (1) 1950 soil & tx for PCN-R S .aureus => replac

e by methicillin / cephalosporin due to toxicity => 1980 steady increased of R strain after large use

(2) inhibition of cell wall: block trans-glycosylation by binding to D-ALA-D-ALA terminal of pentapeptide c stable complex => could not processed by glycosyl-transferase & interrupt cooperation of murein monmers into growing peptidoglycans => interrupt of cell wall synthesis

Antimicrobial activity

Broad spectrum of activity against of Gm(+):

(1) staphylococci: S. aureus, S. epidermidis, S. sapr

ophyticus, S. haemolyticus, S. hominis

(2) enterococci: E. faecalis, E. faecium

(3) streptococci: S. pneumoniae, GAS, GCS, GGS, S.

bovis, viridans group

(4) L. monocytogenes

(5) Gm(+) anaerobes: Peptostreptococci, Actinomyces, Propionibacterium, Clostridium spp

Adverse effects 1. Recommendation for a serum target level <40~50μg/m

L for ototoxicity (vertigo / tinnitus): rare; but augmentation by AG co-administration

2. Synergisitc nephrotoxic effect by vancomycin & AG: 14~20%

3. Infusion-related reactions: most; red-neck or red-man Sx => rash or pruritus over head, face, neck, upper trunk +/- hypotension, angioedema; 3.4~11.2% & histamin release from basophil / mast cell

4. Neutropenia: 1~2% after long-term use (>6.2 months) and suggest monitor WBC 2 weeks later

5. Pregnancy C: safe during 2nd / 3rd trimesters 6. Treatment of C. difficile- related diarrhea by vancomyci

n => might induce C. difficle colitis also

Clinical uses

1. Endocarditis: drug choice for MRSA (4~6 weeks); plus GM or RIF for native valve type

2. Meningitis / ventriculitis: combined c 3 cefa (cefotaxime / ceftriaxone) for pneumococcal meningitis

3. Osteomyelitis: 4~6 weeks plus complete surgical debridement for successful outcome

4. Pseudomembraneous colitis: 7~10D oral vancomycin for C. difficle / S. aureus related colitis

5. Febrile neutropenia: controversial 6. Prophylaxis: for endocarditis while GU / GI pro

cedure on cardiac dz

Quinolones

1. 1962 nalidixic acid => 1970s oxolinic acid & cinoxacin => 1980s FQ derivative

2. Broad spectrum of activity, good oral absorption, good tolerability

3. Temafloxacin, sparfloxacin, grepfloxacin, trovafloxacin removed from market due to toxicity

4. 4. mechanism of action: work on DNA gyrase (gyrA / B) & topo-isomerase IV (parC / E)