AMINOGLYCOSIDES, MACROLIDES, METRONIDAZOLE, CLINDAMYCIN, VANCOMYCIN

Erythromycin, amikacin, vancomycin, clindamycin

AMINOGLYCOSIDES• Streptomycin 1943; Strept.

griseus• Neomycin 1949; Strept. fradiae• Paromomycin (Humagel) 1956; Strept.

rimosus• Kanamycin 1957; Strept.

kanamyceticus • Tobramycin (Nebcin) 1967; Strept.

tenebrarius• Gentamicin (Garamycin) 1963;

Micromonospora purpurea• Sisomicin Micromonospora

inyoensis• Netilmicin (Netromycin) derivative of

Sisomicin• Amikacin (Amikin) derivative of Kanamycin

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 à fetal plasma and

amniotic fluid.

• Excretion– Through the urine by glomerular filtration.

PHARMACOKINETIC PROFILE

DRUG ROA ABSORPTION t ½ (hrs.) PPB

Gentamicin IV/IM Poor 2 <10 Streptomycin IM Poor 2 – 2.5 35Kanamycin IV/IM Poor 2 – 2.5 <10Tobramycin IV/IM Poor 2 <10Amikacin IV/IM Poor 2 – 2.5 <10Netilmicin IV/ IM Poor 2 <10

MECHANISM OF ACTION

• Inhibition of protein synthesis by: 1. Being actively transported through the cell wall. 2. Binding to ribosomal sites à

A. Interference with the initiation complex of peptide formation.

B. Misreading of the genetic code of the mRNA template à incorporation of incorrect AA into the growing polypeptide chains à non-functional or toxic protein.

C. Breaking up of polysomes into non-functional monosomes.

30S Streptomycin30S and 50S Other aminoglycosides

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, high-frequency 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 paralysis4. 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

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 ACTIONInhibits protein synthesis by binding to 23S rRNA component of the 50S subunit à blockade of ribosomal translocation and formation of initiation complexes

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 ACTIVITYDrug ROA Absorption t ½ (hrs)

Erythromycin PO, IVGood 1.5Clarithromycin PO Good 4 – 6 Azithromycin PO Good 10 – 50Roxithromycin PO Good 12Telithromycin PO Good

Antibacterial Activity: Bacteriostatic

CLARITHROMYCIN• Derived from erythromycin by addition of a methyl

group.• Metabolized in the liver into 14-

hydroxyclarithromycin.• 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 INTERACTIONSAdverse Reactions– GI: Anorexia, NAV, diarrhea.– Liver toxicity: Acute cholestatic hepatitis (estolate).– Allergic reactions: Fever, eosinophilia, rashes.

Drug Interactions– Inhibits cytochrome P450 enzyme system à

increased serum concentration of theophylline, oral

anticoagulants, cyclosporine, methylprednisolone, astemizole.

– Increases bioavailability of oral Digoxin à 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.

• Mechanism of Resistance– Resistant strains are less able to reduce the drug

into active intermediate compounds à no accumulation of drug within cell.

MECHANISM OF ACTION

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 à Disulfiram-like effects.– + Coumarin à potentiation of anticoagulant

effect.– + Phenytoin and Phenobarbital à elimination of

metronidazole is accelerated.– + Cimetidine à decreased metronidazole plasmal

clearance.– + Lithium à 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 à 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: BacteriostaticPharmacokinetics:• 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 PCN-allergic 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.

VANCOMYCINSource: Streptococcus orientalisChemistry: Glycopeptide with a mol. wt. of 1449.Mechanism of action:

Inhibits cell wall synthesis by binding to D-Ala-D-Ala terminus of the peptidoglycan pentapeptide à inhibits transglycosylase à prevents further elongation of peptidoglycan à weakening of peptidoglycan à cell susceptible to lysis.

MECHANISM OF ACTION

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 à loss of hydrogen bond that facilitates high-affinity binding of Vancomycin to its target à 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 USESDrug 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.