Aminoglycosides | Antibiotics | Drugs

AMINOGLYCOSIDES, MACROLIDES, METRONIDAZOLE, CLINDAMYCIN, VANCOMYCIN • Erythromycin, amikacin, vancomycin, clindamycin AMINOGLYCOSIDES • Streptomycin griseus • Neomycin fradiae • Paromomycin

(Humagel) Strept. rimosus • Kanamycin kanamyceticus • Tobramycin (Nebcin) tenebrarius • Gentamicin (Garamycin) Micromonospora purpurea • Sisomicin inyoensis • Netilmicin (Netromycin) of Sisomicin • Amikacin (Amikin) Kanamycin 1943; Strept. 1949; Strept. 1956; 1957; Strept. 1967; Strept. 1963; Micromonospora derivative derivative of






MECHANISM OF ACTION • Inhibition of protein synthesis by: 1. Being actively transported through the cell wall. 2. Binding to ribosomal sites ◊ A. Interference with the initiation complex of peptide formation. B. Misreading of the genetic code of the mRNA template ◊ incorporation of incorrect AA into the growing polypeptide chains ◊ nonfunctional or toxic protein. C. Breaking up of polysomes into nonfunctional monosomes. 30S 30S and 50S Streptomycin Other aminoglycosides

NOMENCLATURE AND PROPERTIES • Nomenclature – “-mycin” Streptomyces – “-micin” Micromonospora • Physical and Chemical Properties – Compounds with 2 or more aminosugars linked by glycosidic bonds to an aminocyclitol group (hexose ring): streptidine (streptomycin) or 2-deoxystreptamine. – Water-soluble, stable in solution, more active at alkaline pH. POST-ANTIBIOTIC EFFECT -its antibacterial activity persists beyond the time during which measurable drug is present CONCENTRATION-DEPENDENT KILLING -increasing concentrations kill an increasing proportion of bacteria and at a more rapid rate ADMINISTRATION, DISTRIBUTION, AND EXCRETION • Administration – Must be given parenterally to achieve adequate serum levels except Neomycin, Kanamycin, and Paromomycin. • Distribution – Penetrate most body fluids well except CSF where penetration is poor. – High concentration found in renal cortex and in the endolymph and perilymph of the inner ear. – Cross the placental barrier ◊ fetal plasma and amniotic fluid. Excretion – Through the urine by glomerular filtration.

MECHANISMS OF RESISTANCE • Impaired intracellular transport – Absent oxygen-dependent transport system for aminoglycoside. • Altered ribosomal binding site – Lowered affinity of 30S ribosomal subunit binding site to aminoglycoside as a result of mutation. Inactivation of the drug my microbial enzymes – Production of enzymes that inactivate the drug by adenylylation, acetylation, or phosphorylation.

ANTIMICROBIAL ACTIVITY & ADVERSE REACTIONS • Antimicrobial Activity: Bactericidal • Adverse Reactions 1. Ototoxicity Vestibular damage: Vertigo, ataxia, loss of balance. Cochlear damage: Tinnitus, highfrequency hearing loss. 2. Nephrotoxicity: Proteinuria, cylindruria, and inability to concentrate the urine. Risk factors: Advanced age, preexisting renal disease, concurrent use of Vancomycin, Amphotericin B, Cephalothin, Cisplatin, Cyclosporine. 3. Neuromuscular paralysis 4. Allergic reaction: Contact dermatitis CLINICAL USES • For the treatment of infections caused by aerobic or facultative gm (-) bacilli: Gentamicin, Tobramycin, Amikacin, Netilmicin • For Ps. aeroginosa infection: In comb. with PCN, Ceftazidime, Imipenem,Aztreonam. • Drug of choice for tularemia, plague, and brucellosis (with PCN): Streptomycin • Drug of choice for enterococcal endocarditis: Streptomycin or Gentamicin with PCN G

DRUG ROA ABSORPTION t ½ (hrs.) IV/IM IM IV/IM IV/IM IV/IM Poor Poor Poor Poor Poor 2 2 – 2.5 2 – 2.5 2 2 – 2.5 PPB <10 35 <10 <10 <10

Gentamicin Streptomycin Kanamycin Tobramycin Amikacin

MACROLIDES • Erythromycin: Stearate, ethyl succinate, estolate, gluceptate, lactobionate (1952; Streptomyces erythreus) • Clarithromycin • Azithromycin • Roxithromycin • Dirithromycin Chemistry: – Macrocyclic lactone ring with 1 or more deoxy sugars: Desosamine or cladinose. – Poorly absorbed in water; readily dissolved in organic solvents. – Stable at 4oC; loses activity at 20oC and at acid pH. MECHANISM OF ACTION Inhibits protein synthesis by binding to 23S rRNA component of the 50S subunit ◊ blockade of ribosomal translocation and formation of initiation complexes

Allergic reactions: Fever, eosinophilia, rashes.

Drug Interactions – Inhibits cytochrome P450 enzyme system ◊ increased serum concentration of theophylline, oral anticoagulants, cyclosporine, methylprednisolone, astemizole. – Increases bioavailability of oral Digoxin ◊ increased serum conc. CLINICAL USES • Drug of choice for Mycoplasma pneumonia, Legionella pneumonia, pertussis, diphtheria, chancroid, Campylobacter enteritis, chronic prostatitis due to Chlamydia, and Chlamydia trachomatis infections during pregnancy and childhood. • For prophylaxis against endocarditis during dental procedures in patients with valvular heart disease.

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 • Reduced permeability of the cell membrane. • Production (by enterobacteriaceae) of esterases that hydrolyze the macrolides. • Modification of the ribosomal binding site (ribosomal protection) by chromosomal mutation or by a macrolide-inducible or constitutive methylase. PHARMACOKINETIC PROFILE & ANTIMICROBIAL ACTIVITY Drug ROA Absorption t ½ (hrs) Erythromycin Clarithromycin Azithromycin Roxithromycin Telithromycin PO, IVGood PO Good PO Good PO Good PO Good 1.5 4–6 10 – 50 12

Mechanism of Resistance – Resistant strains are less able to reduce the drug into active intermediate compounds ◊ no accumulation of drug within cell.


Antibacterial Activity: Bacteriostatic CLARITHROMYCIN • Derived from erythromycin by addition of a methyl group. • Metabolized in the liver into 14hydroxyclarithromycin. • Low incidence of GI intolerance. • Less frequent dosing AZITHROMYCIN • Derived from erythromycin by addition of a methylated nitrogen into the 15-atom lactone ring. • Long half-life (2-4 days). • Does not inactivate cytochrome P450 enzymes. A D R & DRUG INTERACTIONS Adverse Reactions – GI: Anorexia, NAV, diarrhea. – Liver toxicity: Acute cholestatic hepatitis (estolate).

PHARMACOKINETICS, ANTIMICROBIAL ACTIVITY, & ADR Pharmacokinetics • 85% absorbed after oral administration; <20% PPB. • May be given orally, IV or by rectal suppository. • Widely distributed in tissues and fluids. • Metabolized in liver; excreted in urine. • t1/2: 7.5 hours. Antimicrobial Activity: Bactericidal Adverse Reactions: • NAV, anorexia, unpleasant metallic taste. • Neurotoxicity manifested by sensory neuropathy, ataxia, encephalopathy, and seizures. • Stomatitis, pancreatitis, dark or reddish-brown urine. DRUG INTERACTIONS & CLINICAL USES • Drug Interactions – + Alcohol ◊ Disulfiram-like effects. – + Coumarin ◊ potentiation of anticoagulant effect. – + Phenytoin and Phenobarbital ◊ elimination of metronidazole is accelerated.

– – •

+ Cimetidine ◊ decreased metronidazole plasmal clearance. + Lithium ◊ accelerated lithium toxicity.

Clinical Uses – Drug of choice for amoebiasis, giardiasis, and urogenital trichomoniasis. – 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. 3. Enzymatic inactivation of Clindamycin. ANTIMICROBIAL ACTIVITY, PHARMACOKINETICS, & ADR Antimicrobial Activity: Bacteriostatic Pharmacokinetics: • Well absorbed PO; 60-90% PPB. • Widely distributed in tissues and body fluids. • Metabolized in liver; excreted through bile & urine; t1/2: 2.5 h. Adverse Reactions • GI: NAV, diarrhea, epigastric pain. • Allergic reactions: Rashes, fever. • Reversible elevations of SGOT and SGPT. • Pseudomembranous colitis secondary to overgrowth of Clostridium difficile. CLINICAL USES • For the treatment of anaerobic intrabdominal and pelvic infections especially those involving B. fragilis (with aminoglycoside or aztreonam). • For the treatment of actinomycosis in PCNallergic patients. • For the treatment of infections due to Staph. aureus or Strep, like osteomyelitis and septic arthritis as alternative drug to b-lactam antibiotics. • Prophylaxis of endocarditis in patients with valvular heart disease undergoing dental procedure. VANCOMYCIN Source: Streptococcus orientalis Chemistry: Glycopeptide with a mol. wt. of 1449. Mechanism of action: Inhibits cell wall synthesis by binding to D-Ala-DAla terminus of the peptidoglycan pentapeptide ◊ inhibits transglycosylase ◊ prevents further elongation of peptidoglycan ◊ weakening of peptidoglycan ◊ cell susceptible to lysis.

MECHANISM OF RESISTANCE, ANTIMICROBIAL ACTIVITY, & PHARMACOKINETICS Mechanism of Resistance: - Modification of D-Ala-D-Ala binding site of the peptidoglycan in which D-Ala is replaced by D-lactate ◊ loss of hydrogen bond that facilitates high-affinity binding of Vancomycin to its target ◊ loss of activity. Antimicrobial Activity: Bactericidal Pharmacokinetics: • Poorly absorbed PO --> given parenterally by IV. • Widely distributed to tissues; 55% PPB. • Excretion by glomerular filtration. • t1/2: 7-8 hours. ADVERSE DRUG REACTIONS • Phlebitis at site of injection. • • Fever and chills. “Red man” or “red neck” syndrome: Tingling, erythema, flushing of the face, neck, and thorax secondary to the release of histamine. Ototoxicity and nephrotoxicity especially in the elderly, those with impaired renal function, and those receiving aminoglycosides concomitantly.

CLINICAL USES Drug of choice in: • Infections caused by methicillin-resistant strains of Staph. aureus, Staph. epidermidis, and other coagulase-negative staphylococci. • Sepsis and endocarditis caused by Staph species or Streptococci in patients allergic to PCN and cephalosporins. Enterococcal infections in PCN-allergic patients. Diphtheroid infections. Seriously ill patients with Clostridium difficile colitis.

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