Antimicrobial Agents

Antimicrobial vs Selection of Antimicrobials Microbial Resistance Complications of AB Prophylactic Empiric

Antibiotic
Antimicrobial: any substance that
inhibits or kills m.o. w/o harming the
host
Antibiotics: natural or semisynthetic
antimicrobials (ABs are a type of
antimicrobials)
m.o. related factors Patient-related factors Drug-related factors therapy therapy therapy
1. Gram stain: used as a preliminary rapid assessment (e.g. G+ve 1. Site of infection: 1. Safety (e.g. ototoxicity of aminglycosides) Causes: 1. Direct toxic effect: Used w/ caution when the • Given before
→ penicillins, G-ve → quinolones) ◦ BBB penetration is affected by ◦ aminoglycosides → oto & benefits outweigh the risks identification of the
2. Cost (1) Naturally resistant strains (e.g. vancomycin-resistant G-ve
lipophilicity, mwt & pp binding nephrotoxicity Examples: m.o.
2. Culture of the m.o. ◦ meningitis (inflammation) → ↑ BBB 3. Bactericidal vs bacteriostatic bacteria ) ◦ chloramphenicol → grey baby
1. to prevent streptococcal • Broad spectrum
permeability → ↑ penicillin penetration A. bactericidal requires actively replicating m.o (2) Spontaneous mutation syndrome infections → rheumatic heart
3. Detection of microbial antigens using PCR (e.g. hepatitis) • Used for severe
◦ prostate → ↓ penetration due to acidic Therefore, combination of cidal + static → (3) Acquired resistance (i.e. from another organism) 2. Allergic rxn (hypersensitivity) disease
medium antagonism infections that
◦ penicillins 2. to prevent TB or meningitis require immediate
2. Immune system B. combination of 2 bactericidal agents → ↑ in individuals who are in
Forms of resistance: ◦ sulfonamides ttt
3. Renal function resistance, superinfection & toxicity → should close contact w/ patients
be used w/ caution (e.g. B-lactams + 1. Altered targets (e.g. alteration of DNA gyrase → resistance to 3. Superinfections:
4. Hepatic function aminoglycosides) fluoroquinolones) 3. prior to prosthetic implant
◦ due to long-term use of broad surgeries (e.g. artificial heart
5. Age 2. Decreased accumulation of the drug due to: spectrum AB → resistance valves or dental prosthesis)
6. Pregnancy & lactation ◦ ↓ permeability (e.g. B-lactams cannot pass through the porins in 4. immunocompromised
the LPS of G-ve bacteria) patients
◦ ↑ efflux (e.g. tetracyclines)
3. Enzymatic deactivation of the drug (e.g. B-lactamase)

Classification of Antibacterial Agents

Class
1- Inhibitors of Cell Wall Synthesis 2- Inhibitors of Cell membrane function
Beta-Lactams Vancomycin Carbapenems Monobactams Fosfomycin Isoniazide (INH) Ethambutol
Penicillins Cephalosporins
General • Highly selective cuz human cells lack cell walls • Same as penicillins MOA: Synthetic β-lactams Aztreonam (IV, IM): • Bactericidal synthetic Active against mycobacterium TB
properties • Bactericidal → therefore, they require actively proliferating bacteria → • cephalosporins are derived from Inhibits polymerization of the • active against pseudomonas derivative of phosphonic acid
antagonized by bacteriostatic cephalosporium mold cell wall e.g. imipenem, meropenem & TB therapy consists of:
ertapenem • Not active against G+ve or • unique structure → no cross
• cephamycins are derived from streptomyces 1. Isoniazide (INH)
anaerobes reactivity → used in case of
Uses: 2. Rifampicin (RNA synthesis inhibitor)
MOA Inhibit penicillin-binding proteins (PBPs) which regulate the cross-linking of peptidoglycan → exposure of the cell membrane (osmotically • MRSA & MRE→ Imipenem (IV): • ↓ immunogenicity → alternative hypersensitivity
unstable) → cell lysis
bacteremia, endo-carditis, broad-spectrum (including to the previous drugs in case of 3. Ethambutol or Pyrazinamide
peritonitis, pneumonia, pseudomonas) → empiric therapy in allergy Uses:
Resistance 1. Production of β-lactamase Same as penicillins, but they are less susceptible to critical cases UTIs (E.coli & E. fecalis)
etc..
2. Camouflaged target (PBP) → penicillin cannot bind to PBPs (e.g. MRSA & MRE) β-lactamase → no need for clavulanic a'
• β-lactam allergic patients Imipenem is taken in combination
3. ↓ permeability of the drug (e.g. porins in G-ve)
w/ cilastatin (why?)
4. Efflux pumps Resistance: • Imipenem is metabolized by
VRSA & VRE dehydropeptidase enzyme in the
Spectrum • G+ve → susceptible A) First generation
renal PCT → nephrotoxic metabolite
• G-ve → not susceptible due to LPS membrane G+ve & some G-ve
• Cilastatin inhibits dehydropeptidase
Cannot cross the BBB
e.g.
• Cefadroxil (Duricef) → oral
Types A) Natural penicillins: • Cephalexin → oral
1. Benzylpenicillin = penicillin G (IV & IM) • Cephradine (Velosef) → parenteral
◦ short duration
◦ acid unstable B) Second generation
◦ β-lactamase sensitive Wider spectrum of activity against G-ve
◦ unstable in solution form (must be freshly prepared) Unreliable CSF penetration
2. Phenoxymethylpenicillin = penicillin V (oral) e.g.
◦ acid stable → oral • Cefaclor → oral
• Cefuroxime → oral
B) Semisynthetic penicillins (by altering the side chain):
• Cefoxitine (cephamycin not cephalosporin) →
1. β-lactamase resistant penicillins → active against staph. (e.g. methicillin &
parenteral
cloxacillin)
2. Extended spectrum penicillins → active against G-ve & G+ve C) Third generation:
◦ Aminopenicillins (ampicillin & amoxicillin) G+ve, G-ve & anaerobic m.o.
◦ carbenicillin & piperacillin → active against pseudomonas highly resistant to β-lactamase
penetrate BBB
C) β-lactamase inhibitors combinations: parenteral administration
1. amoxicillin + clavulanic a' = Augmentin e.g. ceftriaxone & cefotaxime
2. ampicillin + sulbactam = Unasyn
3. piperacillin + tazobactam = Zosyn (IV) D) Fourth generation:
wider spectrum
N.B. the β-lactamase inhibitor has no AB activity on its own
parenteral administration
reserved for severe infections
e.g. Cefepime → active against pseudomonas
Uses • Natural penicillins → G+ve • G-ve bacterial meningitis → ceftriaxone
• penicillinase resistant (e.g. methicillin) → G+ve • gonorrhea
• aminopenicillins → G+ve & G-ve but not pseudomonas • UTI
• extended spectrum (e.g carbenicillin & ticarcillin) → G-ve & pseudomonas • MRSA
N.B. some strains of staph. & enterococci became resistant to methicillin due to • mixed infection esp. anaerobes → 3rd gen.
camouflaged PBPs → MRSA & MRE
Adverse 1) Hypersensitivity: ranging from rashes to angioedema & anaphylaxis → Same as penicillins but less risk of hypersensitivity
effects therefore, SC skin testing is a must before parenteral administration
cross reactivity is observed among natural & semisynthetic penicillins Disadv: most cephalosporins have low oral activity
→ IV or IM
2) GIT disturbance & diarrhea due to normal flora disruption
3) Nephrotoxicity (uncommon)
4) Neurotoxicity: GABAergic inhibition → used w/ caution with epileptic patients
5) ↓ blood cells count (irrelevant)
Pharmaco • Absorption • Poor oral absorption (except for some 1st & 2nd
kinetics ◦ broad spectrum → kills gut flora generation drugs)
◦ taken on empty stomach (↓ gastric acidity) • renal elimination
• Distribution
◦ Cannot reach CSF unless there is inflammation (meningitis) Ceftriaxone:
◦ Cannot reach prostate • can cross the BBB
• biliary elimination → used in renally impaired
patients
• long t1/2
Class
3- Protein Synthesis Inhibitors 4- Inhibitors of Nucleic Acid 5- Antimetabolites (anti-folates)
30 S 50 S Synthesis
Tetracyclines Aminoglycosides Glycyl- Macrolides Lincosamides Chloramphenicol Quinolones Rifamycins Sulfonamides Trimethoprim Cotrimoxazole Dapson
cyclines
MOA Bind to 30S subunit → Bind to 30S subunit → interfere w/ the assembly of ____ Bind irreversibly to 50S Bind to 50S Binds to 50S Inhibition of: RNA polymerase Compete w/ PABA → inhibit DHFR inhibitor Combination of Similar to sulfa
prevent binding of tRNA to ribosomes (i.e. prevent binding of 30S & 50S) → inhibit the 1. Topoisomerase II (gyrase) in G-ve bacteria inhibitor dihydropteroate synthase trimethoprim + drugs
the mRNA-ribosome cpx translocation of protein 2. Topoisomerase IV in G+ve bacteria sulfamethoxazole in a
bacterioSTATIC BacteriCIDAL bacterioSTATIC bacterioSTATIC bacterioSTATIC e.g. Rifampicin & bacterioSTATIC ratio of 1:5
bacteriCIDAL Rifapentin (longer
Examples Doxycycline (Vibramycin) Can be combined w/ β-lactams (as both are CIDAL) 1) Clarithromycin → H. Clindamycin (Dalacin) • Broad spectrum First generation: nonfluorinated FQ t1/2) Spectrum: Similar to sulfonamides Advantages: Uses:
demclocycline Pylori • Reserved for life-threatening nalidixic acid → narrow spectrum (G-ve only) • G+ve, G-ve (shigella & E.coli) • synergism Leprosy
Broad spectrum • used in dental Uses: TB &
minocycline infections for which no • Chlamydia trachomatis (STD) • ↓ resistance
procedures & buccal leprosy
2) Azithromycin
Uses broad spectrum → reserved Uses: infections alternatives exist Second generation: • potent AB effect
1) Streptomycin → TB, plague & tularemia (Zithromax)→ Ciprofloxacin & norfloxacin → active against G-ve
for severe infections • active against Adverse effects: Uses: • both have similar
Respiratory tract & atypical bacteria t1/2
• RTIs 2) Neomycin (Entocid, Bacitracin) & Kanamycin infections (MRSA) anaerobes LME inducer • Meningitis (can cross the BBB)
• UTIs (Kenacomb) → too toxic for parenteral use → taken • UTIs
Third generation: Uses:
• Acne orally or topically → intestinal & skin infections • Sulphasalazine → intestinal
Levofloxacin (respiratory FQ) → RTIs • prostate & vaginal
infections (e.g. ulcerative colitis)
• Gonorrhea 3) Gentamycin (Garamycin) → parenterally for infections
due to its anti-inflammatory &
severe infections Fourth generation: immunosupressant effects • respiratory, intestinal
Moxifloxacin → active against G+ve , G-ve & & UTIs
4) Amikacin → gentamycin-resistant infections • Topical uses
anaerobes
5) Tobramycin (Tobrex eye drops) → active against
N.B. FQs are alternatives to B-lactams in case of
pseudomonas
allergy
Pharmaco • Can cross the BBB → ttt Poor oral absorption → parenteral or topical ____ ____ ____ Form cpx w/ divalent ions (e.g. Ca) → ↓ absorption ____ ____
kinetics of meningitis
• Can reach the prostate CYP inhibitors → risk of drug interactions
→ ttt of prostatitis
Adverse • Bind to Ca in bones & • Ototoxicity • Broad spectrum → • ↓ blood count → CI in anemia • Phototoxicity • Nausea, vomiting & headache • Megaloblastic
effects teeth • Nephrotoxicity kills gut flora & leukemia • Cardiotoxicity → torsade de pointes • Serious SE → stop administration anemia (esp. when
• CI in pregnancy & • Neurotoxicity • CYP 450 inhibitors → • CI in pregnancy & infants → • Joint swelling combined w/ MTX)
◦ Crystalluria (CI in urolithiasis)
children • allergic rxn drug interactions w/ grey baby syndrome due to low • CI in pregnancy • CI in pregnancy →
◦ Hypersensitivity
• drug food interaction w/ warfarin, digoxin, etc... capacity of glucuronidation neural tube defects
◦ plasma protein displacement→ can
Ca
displace bilirubin → kernicterus → CI
in infants, pregnancy & breastfeeding
Selectivity • Selective cuz bacterial ribosomes (30S & 50S) differ structurally from mammalian ribosomes (40S & 60S) _____ _____
• at high doses → interact w/ human ribosomes → toxicity
 Indication AB of choice
Respiratory tract infections Azithromycin (Zithromax)
Levofloxacin (resp. FQ)
H. Pylori Clarithromycin
Chlamydia trachomatis Sulfonamides
Pseudomonas Imipenem
Aztreonam
Cefepime (4th gen.)
Piperacillin, Carbenicillin & Ticarcillin
Tobramycin
Meningitis Ceftriaxone & Cefotaxime (3rd gen. cephalo)
(can cross the BBB)
tetracyclines
Sulfonamides (sulfadiazine)
Prostatitis Tetracyclines
Cotrimoxazole
Infections in renally Ceftriaxone (due to biliary elimination)
impaired patients
Anaerobes Ceftriaxone & Cefotaxime (3rd gen. cephalo)
Lincosamides (Clindamycin)
Moxifloxacin (4th gen. FQ)
Gonorrhea Tetracyclines
cephalosporins
MRSA Vancomycin
cephalosporins
Macrolides (azithro)
TB Streptomycin
Isoniazide + Rifampicin + Ethambutol / Pyrazinamide
Leprosy Rifampicin & Rifapentine
Dapson
Tularemia (rabbit fever) Streptomycin
Buccal & dental infections Clindamycin (Dalacin)
Empiric therapy in critical Imipenem (IV)
cases (e.g. accidents)
UTIs Fluoroquinolones (cipro or nalidixic a')
Tetracyclines
sulfonamides
Cotrimoxazole (Septrin)
Fosfomycin
Safe in pregnancy B-lactams (penicillins & cephalo)
Ulcerative colitis Sulphasalazine (due to its anti-inflammatory effect)