tetracycline medication.These effects are attributable to direct local irritation of the intestinal tract.Nausea,anorexia,and diarrhea can usually be controlled by administering the drug with food or carboxymethylcellulose,reducing drug dosage,or discontinuing the drug. Tetracyclines modify the normal flora,with suppression of susceptible coliform organisms and overgrowth of pseudomonas,proteus,staphylococci,resistant coliforms,clostridia,and candida.This can result in intestinal functional disturbances, anal pruritus,vaginal or oral candidiasis,or enterocolitis with shock and death. B.BONY STRUCTURES AND TEETH Tetracyclines are readily bound to calcium deposited in newly formed bone or teeth in young children.When a tetracycline is given during pregnancy,it can be deposited in the fetal teeth,leading to fluorescence,discoloration,and enamel dysplasia;it can also be deposited in bone,where it may cause deformity or growth inhibition.If the drug is given for long periods to children under 8 years of age,similar changes can result. C.LIVER TOXICITY Tetracyclines can probably impair hepatic function,especially during pregnancy,in patients with preexisting hepatic insufficiency and when high doses are given intravenously.Hepatic necrosis has been reported with daily doses of 4 g or more intravenously. D.KIDNEY TOXICITY Renal tubular acidosis and other renal injury resulting in nitrogen retention have been attributed to the administration of outdated tetracycline preparations.Tetracyclines given along with diuretics may produce nitrogen retention.Tetracyclines other than doxycycline may accumulate to toxic levels in patients with impaired kidney function. E.LOCAL TISSUE TOXICITY Intravenous injection can lead to venous thrombosis.Intramuscular injection produces painful local irritation and should be avoided. F.PHOTOSENSITIZATION Systemically administered tetracycline,especially demeclocycline,can induce sensitivity to sunlight or ultraviolet light,particularly in fair-skinned persons. G.VESTIBULAR REACTIONS Dizziness,vertigo,nausea,and vomiting have been noted particularly with doxycycline at doses above 100 mg.With dosages of 200-400 mg/d of minocycline, 35-70%of patients will have these reactions. MACROLIDES
tetracycline medication. These effects are attributable to direct local irritation of the intestinal tract. Nausea, anorexia, and diarrhea can usually be controlled by administering the drug with food or carboxymethylcellulose, reducing drug dosage, or discontinuing the drug. Tetracyclines modify the normal flora, with suppression of susceptible coliform organisms and overgrowth of pseudomonas, proteus, staphylococci, resistant coliforms, clostridia, and candida. This can result in intestinal functional disturbances, anal pruritus, vaginal or oral candidiasis, or enterocolitis with shock and death. B. BONY STRUCTURES AND TEETH Tetracyclines are readily bound to calcium deposited in newly formed bone or teeth in young children. When a tetracycline is given during pregnancy, it can be deposited in the fetal teeth, leading to fluorescence, discoloration, and enamel dysplasia; it can also be deposited in bone, where it may cause deformity or growth inhibition. If the drug is given for long periods to children under 8 years of age, similar changes can result. C. LIVER TOXICITY Tetracyclines can probably impair hepatic function, especially during pregnancy, in patients with preexisting hepatic insufficiency and when high doses are given intravenously. Hepatic necrosis has been reported with daily doses of 4 g or more intravenously. D. KIDNEY TOXICITY Renal tubular acidosis and other renal injury resulting in nitrogen retention have been attributed to the administration of outdated tetracycline preparations. Tetracyclines given along with diuretics may produce nitrogen retention. Tetracyclines other than doxycycline may accumulate to toxic levels in patients with impaired kidney function. E. LOCAL TISSUE TOXICITY Intravenous injection can lead to venous thrombosis. Intramuscular injection produces painful local irritation and should be avoided. F. PHOTOSENSITIZATION Systemically administered tetracycline, especially demeclocycline, can induce sensitivity to sunlight or ultraviolet light, particularly in fair-skinned persons. G. VESTIBULAR REACTIONS Dizziness, vertigo, nausea, and vomiting have been noted particularly with doxycycline at doses above 100 mg. With dosages of 200-400 mg/d of minocycline, 35-70% of patients will have these reactions. MACROLIDES
INTRODUCTION The macrolides are a group of closely related compounds characterized by a macrocyclic lactone ring (usually containing 14 or 16 atoms)to which deoxy sugars are attached.The prototype drug,erythromycin,which consists of two sugar moieties attached to a 14-atom lactone ring,was obtained in 1952 from Streptomyces erythreus. Clarithromycin and azithromycin are semisynthetic derivatives of erythromycin. ERYTHROMYCIN Chemistry The general structure of erythromycin is shown above with the macrolide ring and the sugars desosamine and cladinose.It is poorly soluble in water (0.1%)but dissolves readily in organic solvents.Solutions are fairly stable at 4 C but lose activity rapidly at 20 C and at acid pH.Erythromycins are usually dispensed as various esters and salts. Antimicrobial Activity Erythromycin is effective against gram-positive organisms,especially pneumococci, streptococci,staphylococci,and corynebacteria,in plasma concentrations of 0.02-2 mcg/mL.Mycoplasma,legionella,Chlamydia trachomatis,C psittaci,C pneumoniae, helicobacter,listeria,and certain mycobacteria (Mycobacterium kansasii,M scrofulaceum)are also susceptible.Gram-negative organisms such as Neisseria sp, Bordetella pertussis,Bartonella henselae,and B quintana (etiologic agents of cat-scratch disease and bacillary angiomatosis),some rickettsia sp,Treponema pallidum,and campylobacter sp are susceptible.Haemophilus influenzae is somewhat less susceptible. The antibacterial action of erythromycin may be inhibitory or bactericidal, particularly at higher concentrations,for susceptible organisms.Activity is enhanced at alkaline pH.Inhibition of protein synthesis occurs via binding to the 50S ribosomal RNA,which blocks the aminoacyl translocation reaction and formation of initiation complexes (Figure 44-1). Resistance Resistance to erythromycin is usually plasmid-encoded.Three mechanisms have been identified:(1)reduced permeability of the cell membrane or active efflux;(2) production (by Enterobacteriaceae)of esterases that hydrolyze macrolides;and (3) modification of the ribosomal binding site (so-called ribosomal protection)by chromosomal mutation or by a macrolide-inducible or constitutive methylase.Efflux
INTRODUCTION The macrolides are a group of closely related compounds characterized by a macrocyclic lactone ring (usually containing 14 or 16 atoms) to which deoxy sugars are attached. The prototype drug, erythromycin, which consists of two sugar moieties attached to a 14-atom lactone ring, was obtained in 1952 from Streptomyces erythreus. Clarithromycin and azithromycin are semisynthetic derivatives of erythromycin. ERYTHROMYCIN Chemistry The general structure of erythromycin is shown above with the macrolide ring and the sugars desosamine and cladinose. It is poorly soluble in water (0.1%) but dissolves readily in organic solvents. Solutions are fairly stable at 4 °C but lose activity rapidly at 20 °C and at acid pH. Erythromycins are usually dispensed as various esters and salts. Antimicrobial Activity Erythromycin is effective against gram-positive organisms, especially pneumococci, streptococci, staphylococci, and corynebacteria, in plasma concentrations of 0.02-2 mcg/mL. Mycoplasma, legionella, Chlamydia trachomatis, C psittaci, C pneumoniae, helicobacter, listeria, and certain mycobacteria (Mycobacterium kansasii, M scrofulaceum) are also susceptible. Gram-negative organisms such as Neisseria sp, Bordetella pertussis, Bartonella henselae, and B quintana (etiologic agents of cat-scratch disease and bacillary angiomatosis), some rickettsia sp, Treponema pallidum, and campylobacter sp are susceptible. Haemophilus influenzae is somewhat less susceptible. The antibacterial action of erythromycin may be inhibitory or bactericidal, particularly at higher concentrations, for susceptible organisms. Activity is enhanced at alkaline pH. Inhibition of protein synthesis occurs via binding to the 50S ribosomal RNA, which blocks the aminoacyl translocation reaction and formation of initiation complexes (Figure 44-1). Resistance Resistance to erythromycin is usually plasmid-encoded. Three mechanisms have been identified: (1) reduced permeability of the cell membrane or active efflux; (2) production (by Enterobacteriaceae) of esterases that hydrolyze macrolides; and (3) modification of the ribosomal binding site (so-called ribosomal protection) by chromosomal mutation or by a macrolide-inducible or constitutive methylase. Efflux