Tetracyclines, Macrolides, Clindamycin, Linezolid

Streptogramins --- adverse effects

(common) Pain at infusion site Hyperbilirubinemia *Inhibits CYP3A4* Risk for causing AAC

Tetracyclines --- adverse effects: Teeth pigmentation & enamel hypoplasia

(happens in infants and young children). Drug deposition in the bone and primary dentition, during calcification in growing children (no prescription below age 8).

Clindamycin --- resistance: mechanisms

(i) Reduced permeability and increased drug efflux. (ii) Production of esterases that hydrolyze the drug. (iii) Modification of the drug binding site on the ribosomal subunit. Because mechanisms of resistance are the same with the macrolides, cross resistance usually occurs.

Erythromycin --- mechanisms of resistance

(most frequent to least) (i) Reduced drug permeability and increased drug efflux. (ii) Production of esterases that hydrolyze the drug. (iii) Modification of the drug binding site on the ribosomal subunit (e.g. methylation). (iv) In the case of methylase producing bacteria, resistance to antibiotics that bind to the same site will occur (e.g. Clindamycin and Streptogramin B).

Clindamycin --- other clinical uses

*Skin and soft tissue infections caused by streptococci and staphylococci* ------ particularly in patients allergic to penicillins. Sometimes combined with an aminoglycoside or cephalosporin to treat penetrating wounds of the abdomen and gut. *prophylaxis for BE* in patients allergic to penicillin type antibiotics. ------ generally, clindamycin is used interchangeably with azithromycin or clarithromycin for this purpose

Clindamycin --- main use

*severe anaerobic infections* ---- Bacteroides ---- Fusobacterium ---- anaerobic gram-positive cocci ---- Actinomyces ---- some Clostridium perfringens

Ketolides --- chemistry

14-membered ring macrolide replace one sugar in the erythromycin ring with a 3-keto group.

Azithromycin --- chemistry

15-member lactone ring created by adding a methylated nitrogen into the lactone ring (vs. 14-member ring for other macrolides).

Streptogramins --- chemistry

2 families, A & B Streptogramin A family --- Dalfopristin Streptogramin B family --- Quinupristin For clinical use Quinupristin and Dalfopristin are combined in a 30:70 ratio.

Clarithromycin --- chemistry

6-methoxy erythromycin derivative designed to be *acid stable* and exhibit *fewer instances of GI disturbance*

Bacterial ribosome

70S --- 50S --- 30S

Erythromycin --- distribution

Accesses all body fluids except the CSF. Inflammation allows greater tissue penetration.

Protein synthesis in bacteria

Amino acids carried by t-RNAs enter the ribosome and sit on Acceptor site (A-site). Transpeptidase fuses the peptide bond between two amino acids. Uncharged t-RNA is released from the P-site. t-RNA bound to peptide chain moves to P site

Most common macrolide prescribed

Azithromycin --- lack of drug interactions --- easy dosing (one of the most commonly used antibiotics overall)

Ketolides --- elimination

Bile & Urine

Erythromycin --- MOA

Binds to bacterial 50S ribosome. Inhibits protein synthesis by blocking the transpeptidation reaction (step 2). Generally *bacteristatic* may be bactericidal at higher concentrations

Clindamycin --- MOA

Binds to the 50S ribosome at the same site as erythromycin

Streptogramins --- MOA

Both bind to the P-site of the 50S ribosome to block the release of the nascent polypeptides. Their combination is synergistic (Type A changes the conformation of the 50S ribosome to enhance type B binding 100-fold). Their combination is *Bactericidal*

Streptogramins --- metabolization & excretion

Both drugs are rapidly metabolized (0.85-0.7 h half-lives) Eliminated by fecal route

Tetracyclines --- spectrum of activity

Broad spectrum Effective against gram-positive and gram- negative bacteria (both aerobes and anaerobes) also effective against - Rickettsiae - Chlamydiae - Spirochetes (Borrelia burgdorferi only) - Mycoplasma pneumoniae

Erythromycin --- drug of choice for:

Corynebacterial infection (e.g. diphtheria, Corynebacterial sepsis).

Erythromycin --- elimination

Detoxified in the liver (excreted in bile), so may be used in presence of renal dysfunction. Erythromycin is metabolized by P450 enzymes. *Erythromycin metabolites inhibit CYP3A4*

Erythromycin --- adverse drug interactions (partial list)

Digoxin Theophylline Warfarin Cyclosporine, tacrolimus Methylprednisolone HMG-Co A Reductase inhibitors (statins)

Clindamycin --- chemistry

Distinct structure smaller than erythromycin

Tetracyclines --- distribution

Distribute to most tissues. Concentrate in the liver, kidney, spleen and skin and bind to tissues undergoing calcification (e.g. teeth, bones) Penetrate into body fluids, e.g. saliva, pleural fluid, milk, bile Cross the placenta. Poor distribution into CSF and ocular fluids ---- except Minocycline

Ketolides --- distribution

Distributes well into most tissues

Clindamycin --- distribution & half life

Distribution is good in soft and hard tissues including bone. No CSF or brain penetration. 90% protein-bound half-life = 2.5 hours

Azithromycin --- drug interactions

Does not inactivate P450 enzymes in liver (due to structural differences). Free of drug interactions!

Most commonly used tetracycline

Doxycycline --- oral administration + ease of dosing + compatibility with food

Linezolid --- excretion

Drug is excreted both by renal and non-renal routes.

Erythromycin --- antibacterial spectrum

Effective against Gram-positive organisms, similar to Penicillin G. Also effective against --- Spirochetes --- Rickettsia --- Mycoplasma --- Chlamydia Some Gram-negative organisms are also susceptible.

Tetracyclines --- MOA

Enter bacteria through a combination of passive diffusion and active transport. Block protein synthesis by *reversibly* binding to the 30S ribosome --- block t-RNA access to A-site *Bacteriostatic*

Clindamycin --- resistance: organisms

Enterococci and many gram-negative aerobes are intrinsically resistant due to poor permeability of the outer membrane to Clindamycin. C. difficile is also always resistant (even though it's gram positive). Some methicillin resistant S. aureus (MRSA) and erythromycin-resistant S. aureus (ERSA) are also resistant to clindamycin.

Macrolides

Erythromycin (prototype) Clarithromycin Azithromycin

Clindamycin --- adverse effects

GI disturbances ---- nausea and diarrhea Hypersensitivity reactions ---- manifested as a skin rash ---- 10% of patients Less commonly, *Antibiotic-Associated Colitis (AAC)* ----- pseudomembranous colitis ----- caused by overgrowth of Clostridium difficile ----- Treatment: oral administration of Metronidazole or Vancomycin

Tetracyclines --- adverse effects

GI irritation --- most common Hypo-mineralization of bone Teeth pigmentation & enamel hypoplasia Discoloration Renal toxicity Hepatotoxicity Photosensitization of the skin Vestibular reactions

Erythromycin --- adverse effects

GI irritation is the #1 problem (cause of limited use). Liver toxicity ---- Cholestatic jaundice (particularly with erythromycin estolate formulation)

Azithromycin --- clinical uses

Generally the same as other macrolides, except dosing is much easier. Often used for -- upper and lower respiratory tract infections -- otitis -- skin and soft tissue infections -- Chlamydia Both clarithromycin and azithromycin are recommended for prophylactic use against BE (bacterial endocarditis) in patients allergic to penicillins

Tetracyclines --- general clinical uses

Gram-positive and gram-negative bacteria. Thus, tetracyclines may be used in the treatment of infections of the respiratory tract, sinuses, middle ear, urinary tract, intestines. *However, widespread resistance limits their use. It is recommended that infectious agent be tested for tetracycline susceptibility prior to use.*

Streptogramins --- spectrum of activity

Gram-positive cocci ----- except E. faecalis Active against multidrug resistant bacteria, including Streptococci, S. pneumonia, MRSA and VRSA.

Linezolid --- spectrum

Gram-positive organisms (Staph., Strep., Enterococci, Corynebacterium, and Listeria). Moderately active against Mycobacterium tuberculosis.

Linezolid --- adverse effects

Hematologic --- principle toxicity --- reversible and generally mild (e.g. thrombocytopenia, neutropenia). Occasionally minor GI upset --- nausea and diarrhea. Linezolid is a weak monoamine oxidase inhibitor, so can observe serotonin syndrome in patients taking reuptake inhibitors ----- e.g. antidepressants

Streptogramins --- administration

IV

Linezolid --- MOA

Inhibits bacterial protein synthesis by binding to the 23S rRNA within the 50S ribosome subunit. Because of its unique mechanism of action, no cross resistance with other 30S or 50S binding drugs. *Bacteriostatic* ---- bactericidal for streptococci

Azithromycin --- pharmacokinetics

Longer half-life (in tissue: 2-4 day) ---- allowing daily dosing 10-100 fold higher concentration in tissues then in serum ----- vs. 1-2 times higher for clarithromycin

Linezolid --- clinical use

MRSA & VRSA VRE (vancomycin-resistant Entercoccus faecium and Enterococcus faecalis) penicillin-resistant streptococci. [Its use should be reserved only for these infections]

Clindamycin --- metabolism & excretion

Metabolized by liver Excreted into bile no adjustment of dose for renal impairment.

Tetracyclines --- *drugs of choice* for

Mycoplasma pneumoniae Rickettsia Chlamydia trachomatis Vibrio cholera Spirochetes --- Borrelia burgdorferi (lyme disease)

Ketolides --- administration

Oral

Clindamycin --- administration

Oral & parenteral Absorbed orally with or without food.

Erythromycin --- absorption

Oral administration ---- erratic absorption orally (food interferes with absorption; stomach acid destroys erythromycin). ---- It is best given on an empty stomach Erythromycin estolate form is best absorbed, but has the most adverse reactions

Linezolid --- administration

Oral administration usually (may also be administered by IV)

Tetracyclines --- adverse effects: Discoloration

Prolonged use of minocycline may cause bluish staining of gums and other organs, such as skin. Staining of gums is permanent.

Streptogramins

Quinupristin-Dalfopristin

Tetracyclines --- mechanisms of resistance

Reduced influx --- altered porin structure --- gram-negative bacteria only Increased active efflux --- plasmid pBR322 -- Cross-resistance between all tetracyclines is not uniform by this mechanism Ribosomal protection --- increased production of proteins that prevent binding to the A-site --- 2nd most common mechanism of resistance. Enzymatic inactivation --- least common

Erythromycin --- resistance

Resistance to erythromycin has become a problem in the clinic. Many Streptococci and Staphylococci are now resistant to this drug. Cross resistance between all macrolides is complete (except for ketolides).

Clarithromycin --- antibacterial spectrum

Same as erythromycin. Includes --- Gram-positive aerobes --- some Gram-negative aerobes such as Hemophilus influenzae --- Mycobacterium avium complex (AIDS patients)

Ketolides --- adverse effects

Same as erythromycin. Inhibits CYP3A4

Clarithromycin --- MOA

Same as erythromycin. Less frequent dosing required than for erythromycin because of a longer half-life (6 h vs. 2h for erythromycin), and the primary metabolite is still active.

Tetracyclines --- adverse effects: Photosensitization of the skin

Severe sunburn can occur (e.g. occurs in 30% of patients treated with Doxycycline).

Clindamycin --- antibacterial spectrum

Similar to erythromycin. *Effective against anaerobic bacteria* ---- Bacteroides (B. fragilis) as well as infections caused by Streptococci and Staphylococci.

Ketolides --- antibacterial spectrum

Similar to other macrolides. Advantage: Because it binds the ribosome with higher affinity and is not a good substrate for efflux pumps, *Telithromycin is useful for macrolide-resistant bacteria*

Clarithromycin --- adverse effects

Similar to those listed for erythromycin. However, clarithromycin causes less GI disturbance than erythromycin. Drug interactions for clarithromycin should be considered the same as for erythromycin.

Ketolides --- drugs

Telithromycin

Tetracyclines --- excretion

Tetracycline & Minocycline --- renal & GI routes Doxycycline & Tigecycline --- non-renal routes --- safe for renal-impaired

Tetracyclines --- prototype drugs + administration

Tetracycline (TC) -- oral Doxycycline (DC) -- oral Minocycline (MOC) -- oral Tigecycline (TGC) -- IV

Tetracyclines --- half life

Tetracycline = 6 hrs --- 4x/day --- protein bound Doxycycline, Minocycline = 12-20 hrs --- 1x/day --- due slow excretion + long t1/2 Tigecycline = 36 hours

Linezolid --- distribution

Widely distributed throughout the body. Half-life = 4-6 hours.

Streptogramins --- resistance

a. Modification of the quinupristin binding site. b. Enzymatic inactivation of dalfopristin. c. Increased efflux of both drugs.

Tetracyclines --- adverse effects: GI irritation

alter normal flora of body, resulting in overgrowth of undesirable microbial strains. Anal pruritis Vaginal and oral candidiasis Enterocolitis [can also result]

Tetracyclines --- chemistry

basic 4 ring structure

Linezolid --- chemistry

belongs to a new class of synthetic oxazolidinones

Ketolides --- clinical uses

currently only recommended for treatment of community acquired pneumonia

Tetracyclines --- adverse effects: Renal toxicity

damage to proximal renal tubules can occur with outdated prescriptions. Tetracyclines should not be used in patients with renal dysfunction.

Tetracyclines --- adverse effects: Vestibular reactions

dizziness, vertigo, nausea and vomiting can occur with high does DOC or MOC treatment

Tetracyclines --- adverse effects: Hepatotoxicity

high doses of tetracyclines, especially in pregnant or hepatic impaired patients

Erythromycin --- chemistry

large cyclic lactone ring (14 member ring)

Streptogramins --- clinical uses

limited solubility and commonly occurring side effects have severely constrained its clinical use. Streptococcus (pyogenes and pneumoniae) infections ---- 2nd line choice) MSRA, VRSA Vancomycin resistant E. faecium ---- not faecalis!

Linezolid --- resistance

mutations in 23S rRNA preventing drug binding

Tigecycline

new drug *Very broad* ---- MRSA ---- VRE Many tetracycline-resistant strains are susceptible to Tigecycline ---- except P. mirabilis and P. aeruginosa, which are intrinsically resistant IV administration only. Use generally reserved for in-patient settings and severe infections where other antibiotics have failed.

Erythromycin --- other clinical uses

respiratory, neonatal, ocular areas, and genital Chlamydia. pneumonia due to S. pneumoniae, Mycoplasma pneumoniae, and Legionella pneumophila. Because of the similar antibiotic spectrum of erythromycin and other macrolides to penicillins, they are often used as substitutes in patients with penicillin allergies

Azithromycin --- antibacterial spectrum

same as clarithromycin

Azithromycin --- MOA

same as erythromycin

Ketolides --- MOA

same as other macrolides except Telithromycin has a higher affinity for the 50S ribosome and is a weaker substrate for the efflux pump.

Tetracyclines --- adverse effects: Hypo-mineralization of bone

should not use during pregnancy or in young children

Tetracyclines --- absorption

varies depending on type of tetracycline and presence of food Doxycycline is the exception ---- 100% absorbed and not affected by food Absorption of all oral tetracyclines is reduced by --- divalent cations (Ca2+, Mg2+, Fe2+) --- Al3+-containing antacid compounds --- alkaline pH

Tetracyclines --- bacterial resistance

widespread