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AMINOGLYCOSIDES, MACROLIDES, Netilmicin IV/ IM Poor 2 <10

METRONIDAZOLE,
CLINDAMYCIN, VANCOMYCIN MECHANISM OF ACTION
• Erythromycin, amikacin, vancomycin, • Inhibition of protein synthesis by:
clindamycin 1. Being actively transported through the cell
wall.
AMINOGLYCOSIDES 2. Binding to ribosomal sites ◊
• Streptomycin 1943; Strept. A. Interference with the initiation complex of
griseus peptide formation.
• Neomycin 1949; Strept. B. Misreading of the genetic code of the mRNA
fradiae template ◊ incorporation of incorrect AA into
• Paromomycin (Humagel) 1956; the growing polypeptide chains ◊ non-
Strept. rimosus functional or toxic protein.
• Kanamycin 1957; Strept. C. Breaking up of polysomes into non-
kanamyceticus functional monosomes.
• Tobramycin (Nebcin) 1967; Strept.
tenebrarius 30S Streptomycin
• Gentamicin (Garamycin) 1963; 30S and 50S Other aminoglycosides
Micromonospora purpurea
• Sisomicin Micromonospora
inyoensis
• Netilmicin (Netromycin) derivative
of Sisomicin
• Amikacin (Amikin) derivative of
Kanamycin

NOMENCLATURE AND PROPERTIES


• Nomenclature
– “-mycin” Streptomyces MECHANISMS OF RESISTANCE
– “-micin” Micromonospora • Impaired intracellular transport
• Physical and Chemical Properties – Absent oxygen-dependent transport system for
– Compounds with 2 or more aminosugars aminoglycoside.
linked by glycosidic bonds to an aminocyclitol
group (hexose ring): streptidine (streptomycin) • Altered ribosomal binding site
or 2-deoxystreptamine. – Lowered affinity of 30S ribosomal subunit
– Water-soluble, stable in solution, more active binding site to aminoglycoside as a result of
at alkaline pH. mutation.

POST-ANTIBIOTIC EFFECT • Inactivation of the drug my microbial enzymes


-its antibacterial activity persists beyond the time during – Production of enzymes that inactivate the drug
which measurable drug is present by adenylylation, acetylation, or
phosphorylation.
CONCENTRATION-DEPENDENT KILLING
-increasing concentrations kill an increasing proportion ANTIMICROBIAL ACTIVITY & ADVERSE
of bacteria and at a more rapid rate REACTIONS
• Antimicrobial Activity: Bactericidal
ADMINISTRATION, DISTRIBUTION, AND • Adverse Reactions
EXCRETION 1. Ototoxicity
• Administration Vestibular damage: Vertigo, ataxia, loss of
– Must be given parenterally to achieve balance.
adequate serum levels except Neomycin, Cochlear damage: Tinnitus, high-
Kanamycin, and Paromomycin. frequency hearing loss.
2. Nephrotoxicity: Proteinuria, cylindruria, and
• Distribution inability to concentrate the urine.
– Penetrate most body fluids well except CSF
where penetration is poor. Risk factors: Advanced age, preexisting renal
– High concentration found in renal cortex and disease, concurrent use of Vancomycin,
in the endolymph and perilymph of the inner Amphotericin B, Cephalothin, Cisplatin,
ear. Cyclosporine.
3. Neuromuscular paralysis
– Cross the placental barrier ◊ fetal plasma and
4. Allergic reaction: Contact dermatitis
amniotic fluid.
CLINICAL USES
• Excretion
• For the treatment of infections caused by aerobic
– Through the urine by glomerular filtration.
or facultative gm (-) bacilli: Gentamicin,
Tobramycin, Amikacin, Netilmicin
PHARMACOKINETIC PROFILE
• For Ps. aeroginosa infection: In comb. with PCN,
DRUG ROA ABSORPTION t ½ (hrs.) PPB Ceftazidime, Imipenem,Aztreonam.
• Drug of choice for tularemia, plague, and
Gentamicin IV/IM Poor 2 <10 brucellosis (with PCN): Streptomycin
Streptomycin IM Poor 2 – 2.5 35 • Drug of choice for enterococcal endocarditis:
Kanamycin IV/IM Poor 2 – 2.5 <10 Streptomycin or Gentamicin with PCN G
Tobramycin IV/IM Poor 2 <10
Amikacin IV/IM Poor 2 – 2.5 <10
MACROLIDES – Allergic reactions: Fever, eosinophilia, rashes.
• Erythromycin: Stearate, ethyl succinate, estolate,
gluceptate, Drug Interactions
lactobionate – Inhibits cytochrome P450 enzyme system ◊
(1952; Streptomyces erythreus) increased serum concentration of theophylline,
• Clarithromycin oral anticoagulants, cyclosporine,
• Azithromycin methylprednisolone, astemizole.
• Roxithromycin – Increases bioavailability of oral Digoxin ◊
• Dirithromycin increased serum conc.

Chemistry: CLINICAL USES


– Macrocyclic lactone ring with 1 or more deoxy • Drug of choice for Mycoplasma pneumonia,
sugars: Desosamine or cladinose. Legionella pneumonia, pertussis, diphtheria,
– Poorly absorbed in water; readily dissolved in chancroid, Campylobacter enteritis, chronic
organic solvents. prostatitis due to Chlamydia, and Chlamydia
– Stable at 4oC; loses activity at 20oC and at acid trachomatis infections during pregnancy and
pH. childhood.

MECHANISM OF ACTION • For prophylaxis against endocarditis during dental


Inhibits protein synthesis by binding to 23S rRNA procedures in patients with valvular heart disease.
component of the 50S subunit ◊ blockade of ribosomal
translocation and formation of initiation complexes METRONIDAZOLE
• Chemistry
– Nitroimidazole compound with a molecular
wt. of 170.

• Mechanism of Action
– Bactericidal activity through 3 steps:
1. Penetration into the bacterial cell.
2. Reductive activation.
3. Toxic effect of the reduced intermediate
products.

MECHANISMS OF RESISTANCE • Mechanism of Resistance


• Reduced permeability of the cell membrane. – Resistant strains are less able to reduce the
• Production (by enterobacteriaceae) of esterases drug into active intermediate compounds ◊ no
that hydrolyze the macrolides. accumulation of drug within cell.
• Modification of the ribosomal binding site
(ribosomal protection) by chromosomal mutation MECHANISM OF ACTION
or by a macrolide-inducible or constitutive
methylase.

PHARMACOKINETIC PROFILE &


ANTIMICROBIAL ACTIVITY
Drug ROA Absorption t ½ (hrs)

Erythromycin PO, IVGood 1.5


Clarithromycin PO Good 4–6 PHARMACOKINETICS, ANTIMICROBIAL
Azithromycin PO Good 10 – 50 ACTIVITY, & ADR
Roxithromycin PO Good 12 Pharmacokinetics
Telithromycin PO Good • 85% absorbed after oral administration; <20%
PPB.
Antibacterial Activity: Bacteriostatic • May be given orally, IV or by rectal suppository.
• Widely distributed in tissues and fluids.
CLARITHROMYCIN • Metabolized in liver; excreted in urine.
• Derived from erythromycin by addition of a • t1/2: 7.5 hours.
methyl group.
• Metabolized in the liver into 14- Antimicrobial Activity: Bactericidal
hydroxyclarithromycin.
• Low incidence of GI intolerance. Adverse Reactions:
• Less frequent dosing • NAV, anorexia, unpleasant metallic taste.
• Neurotoxicity manifested by sensory neuropathy,
AZITHROMYCIN ataxia, encephalopathy, and seizures.
• Derived from erythromycin by addition of a • Stomatitis, pancreatitis, dark or reddish-brown
methylated nitrogen into the 15-atom lactone ring. urine.
• Long half-life (2-4 days).
• Does not inactivate cytochrome P450 enzymes. DRUG INTERACTIONS & CLINICAL USES
• Drug Interactions
A D R & DRUG INTERACTIONS – + Alcohol ◊ Disulfiram-like effects.
Adverse Reactions
– + Coumarin ◊ potentiation of anticoagulant
– GI: Anorexia, NAV, diarrhea.
effect.
– Liver toxicity: Acute cholestatic hepatitis
– + Phenytoin and Phenobarbital ◊ elimination
(estolate).
of metronidazole is accelerated.
– + Cimetidine ◊ decreased metronidazole
plasmal clearance.
– + Lithium ◊ accelerated lithium toxicity.

• Clinical Uses
– Drug of choice for amoebiasis, giardiasis, and
urogenital trichomoniasis. MECHANISM OF ACTION
– Drug of choice for non-specific vaginitis.
– Alternative drug to Vancomycin for C.
difficile colitis.

CLINDAMYCIN
• Chemistry: 7-chloro-7-deoxy derivative of
Lincomycin.
• Mechanism of Action:
Inhibits protein synthesis by binding to the 50S
ribosomal subunit of the bacteria ◊ interferes with
formation of initiation complexes and aminoacyl
translocation reactions.
• Mechanisms of Resistance
1. Mutation of the ribosomal receptor site.
2. Modification of the receptor by a
constitutively expressed methylase. MECHANISM OF RESISTANCE,
3. Enzymatic inactivation of Clindamycin. ANTIMICROBIAL ACTIVITY, &
PHARMACOKINETICS
ANTIMICROBIAL ACTIVITY,
PHARMACOKINETICS, & ADR Mechanism of Resistance:
- Modification of D-Ala-D-Ala binding site of the
Antimicrobial Activity: Bacteriostatic peptidoglycan in which D-Ala is replaced by D-lactate
Pharmacokinetics: ◊ loss of hydrogen bond that facilitates high-affinity
• Well absorbed PO; 60-90% PPB. binding of Vancomycin to its target ◊ loss of activity.
• Widely distributed in tissues and body fluids.
• Metabolized in liver; excreted through bile & Antimicrobial Activity: Bactericidal
urine; t1/2: 2.5 h.
Adverse Reactions Pharmacokinetics:
• GI: NAV, diarrhea, epigastric pain. • Poorly absorbed PO --> given parenterally by IV.
• Allergic reactions: Rashes, fever. • Widely distributed to tissues; 55% PPB.
• Reversible elevations of SGOT and SGPT. • Excretion by glomerular filtration.
• Pseudomembranous colitis secondary to • t1/2: 7-8 hours.
overgrowth of Clostridium difficile.
ADVERSE DRUG REACTIONS
CLINICAL USES • Phlebitis at site of injection.
• For the treatment of anaerobic intrabdominal and
pelvic infections especially those involving B. • Fever and chills.
fragilis (with aminoglycoside or aztreonam).
• For the treatment of actinomycosis in PCN- • “Red man” or “red neck” syndrome: Tingling,
allergic patients. erythema, flushing of the face, neck, and thorax
• For the treatment of infections due to Staph. secondary to the release of histamine.
aureus or Strep, like osteomyelitis and septic
arthritis as alternative drug to b-lactam • Ototoxicity and nephrotoxicity especially in the
antibiotics. elderly, those with impaired renal function, and
• Prophylaxis of endocarditis in patients with those receiving aminoglycosides concomitantly.
valvular heart disease undergoing dental
procedure. CLINICAL USES
Drug of choice in:
VANCOMYCIN • Infections caused by methicillin-resistant strains of
Source: Streptococcus orientalis Staph. aureus, Staph. epidermidis, and other
Chemistry: Glycopeptide with a mol. wt. of 1449. coagulase-negative staphylococci.
Mechanism of action:
Inhibits cell wall synthesis by binding to D-Ala-D- • Sepsis and endocarditis caused by Staph species or
Ala terminus of the peptidoglycan pentapeptide ◊ Streptococci in patients allergic to PCN and
inhibits transglycosylase ◊ prevents further elongation of cephalosporins.
peptidoglycan ◊ weakening of peptidoglycan ◊ cell
susceptible to lysis. • Enterococcal infections in PCN-allergic patients.

• Diphtheroid infections.

• Seriously ill patients with Clostridium difficile


colitis.