Chapter 82 - Bacteriostatic Inhibitors Of Protein Synthesis

CHAPTER 82 BACTERIOSTATIC INHIBITORS OF PROTEIN SYNTHESIS: TETRACYCLINES, MACROLIDES, CLINDAMYCIN, CHLORAMPHENICOL, LINEZOLID, DALFOPRISTIN / QUINUPRISTIN, AND SPECTINOMYCIN All of the drugs discussed inhibit bacterial protein synthesis. - usually bacteriostatic = suppress bacterial growth and replication but do not produce outright kill - suppress bacterial growth by inhibiting protein synthesis - second-line agents, primarily because of emerging resistance or toxicity

I.

TETRACYCLINES

- broad spectrum with principal differences among the group are pharmacokinetic - suppress bacterial growth by inhibiting protein synthesis - selective toxicity is determined by relative inability to cross mammalian cell membranes - mammalian cells lack the energy-dependent transport system to enter bacteria cells - do not actively accumulate drug levels, levels remain too low to be harmful - may be administered orally, IV or IM - oral is preferred, taken on an empty stomach (1 hr before or 2 hrs after a meal) - IM is extremely painful and used rarely 1.

Therapeutic Uses a. Treatment of Infectious Diseases – extensive use has resulted in increasing bacterial resistance - because of microbial resistance, and because antibiotics with greater selectivity and less toxicity are now available, use of tetracyclines have declined - rarely drugs of first choice - first-line drugs for disorders that include: • rickettsial diseases (Rocky Mountain spotted fever, typhus fever) • infections caused by Chlamydia trachomatis (trachoma, lymphogranuloma venereum, cervicitis) • brucellosis • cholera • pneumonia caused by Mycoplasma pneumoniae • Lyme disease • anthrax • gastric infection with H. pylori b. Treatment of Acne – used topically and orally (minimal adverse effects) for severe acne vulgaris

c. Peptic Ulcer Disease – Helicobacter pylori, a bacterium that lives in the stomach, is a major contributing factor d.

Periodontal Disease – doxycycline, minocycline, tetracycline - doxycycline (periostat) is taken orally - benefits result from inhibiting collagenase (enzyme that destroys connective tissue in the gums) and not from killing bacteria - minocycline (arestin) and tetracycline (actisite) are applied topically topical tetracycline - available as a polymer thread which is packed into periodontal pockets and releases drug slowly for 10 days, at which time thread is removed topical minocycline – available as powder composed of “microspheres” and is applied directly into periodontal pockets e.

Rheumatoid Arthritis – minocycline can reduce symptoms

2. Pharmacokinetics - significant differences among the group is in half-life and route of elimination - differences in the extent to which food decreases absorption - widely distributed to most tissues and body fluids - penetration to CSF is poor - inadequate for treating meningeal infections - readily crosses the placenta and enters the fetal circulation - eliminated by kidneys and liver - those excreted by liver into the bile which enters the intestine and most are reabsorbed 3. Absorption – orally effective, should be administered at least 2 hours before or after chelating agents - should not be administered with: calcium supplements milk products (due to calcium content) iron supplements magnesium containing laxatives most antacids (due to magnesium, aluminum or both) 4.

Adverse Effects - gastrointestinal Irritation –epigastric burning, cramps, nausea, vomiting, and diarrhea - diarrhea may result from suprainfections of the bowel (cause of diarrhea must be determined)

- effects on Bones and Teeth – binds to calcium in developing teeth, resulting in yellow or brown discoloration - hypoplasia of enamel may occur - staining is darker with prolonged and repeated treatment - can suppress long-bone growth in premature infants - suprainfection – suprainfections of the bowel produces severe diarrhea and be life threatening - infections caused by C. Difficile are known as antibiotic associated pseudomembranous colitis - overgrowth with fungi (commonly Candida Albicans) may occur in the mouth, pharynx, vagina, and bowel - symptoms include vaginal or anal itching, inflammatory lesions of anogenital region, and a black, furry appearance of the tongue - hepatotoxicity – can case fatty infiltration of the liver, manifests clinically as lethargy and jaundice - pregnant and postpartum women with kidney disease are at high risk - renal toxicity - photosensitivity = avoid prolonged exposure to sunlight, wear protective clothing, and apply sunscreen to exposed skin - vestibular toxicity – manifesting as dizziness, lightheadedness, and unsteadiness - pain

II.

MACROLIDES - broad spectrum that act by inhibiting bacterial protein synthesis

A. ERYTHROMYCIN (EES) – relatively broad spectrum that is preferred or an alternative treatment for a number of infections 1. Therapeutic Uses – treatment of first choice for several infections and may be used as an alternative to penicillin G in patients allergic to penicillins - legionella pneumophila (legionnaires’ disease) - whooping cough (causative agent = bordetella pertussis ) - acute diphtheria and eliminating the diphtheria carrier state - chlamydial infections (urethritis, cervicitis) - pneumonia - substitute for penicillin to treat respiratory tract infections caused by streptococcus - also for preventing recurrences of rheumatic fever and bacterial endocarditis

2. Pharmacokinetics – unstable in stomach acid, therefore, is enhanced by acid-resistant (entericcoating) coatings - food decreases the absorption - readily distributed to most tissues and body fluids - penetration to CSF is poor - crosses placenta but adverse effects on fetus have not been observed - eliminated primarily by hepatic mechanisms - concentrated in the liver then excreted in the bile 3.

Adverse Effects – generally free of serious toxicity - gastrointestinal effects = epigastric pain, nausea, vomiting,

diarrhea - liver injury = symptoms include nausea, vomiting, abdominal pain, jaundice, and elevations in plasma levels of bilirubin and liver transaminases - suprainfections of the bowel - thrombophlebitis B.

OTHER MACROLIDES - all are similar to erythromycin with respect to mechanism of action, antimicrobial spectrum, and resistance 1.

Clarithromycin (Biaxin) – inhibits protein synthesis - approved for respiratory tract infections, uncomplicated infections of the skin and skin structures and prevention of disseminated mycobacterium avium complex infection in HIV patients - also used for H. Pylori infection and as a substitute for penicillin G - well absorbed regardless of the presence of food - elimination is by hepatic metabolism and renal excretion 2.

Azithromycin (Zithromax, Z-Pac) – inhibits protein synthesis - used for respiratory tract infections, chancroid, otitis media, uncomplicated infections of the skin and skin structures - used as a substitute for penicillin G - should be administered 1 hr before or 2 hrs after meals 3. Dirithromycin (Dynabac) – similar to erythromycin with respect to mechanisms of action, antimicrobial spectrum, and clinical effects - indicated for bronchitis, community-acquired pneumonia and skin and soft tissue infections

III.

OTHER BACTERIOSTATIC INHIBITORS

OF

PROTEIN SYNTHESIS

A.

CLINDAMYCIN (CLEOCIN) - can promote severe antibiotic associated pseudomembranous colitis, a condition that can be fatal - inhibits protein synthesis 1. Therapeutic Uses – employed primarily for anaerobic infections outside the CNS (drug does not cross the blood-brain barrier) - preferred drug for abdominal and pelvic infections - substitute for penicillin G - bone and joint infections - skin and soft tissue infections 2.

Pharmacokinetics – may be administered orally, IM and IV - not affected by food - widely distributed to most body fluids and tissues, including synovial fluid and bone - penetration to CSF is poor - undergoes hepatic metabolism and are excreted in urine and bile 3.

Adverse Effects - antibiotic associated pseudomembranous colitis, caused by suprainfections of the bowel - characterized by profuse, watery diarrhea (10 – 20 stools/day which often contain mucus and blood), abdominal pain, fever, and leukocytosis - diarrhea - hypersensitivity reactions (especially rashes) - hepatotoxicity and blood dyscrasias (agranulocytosis, leucopenia, thrombocytopenia) B.

CHLORAMPHENICOL (CHLOROMYCETIN) - broad spectrum with the potential for causing fatal aplastic anemia - limited to serious infections for which less toxic drugs are ineffective - drug of choice for acute typhoid fever but not recommended for routine therapy of typhoid carrier state - lethal to H. Influenzae, an organism that can infect the meninges and other sites - administered orally or by IV - widely distributed to body tissues and fluids - therapeutic concentrations are readily achieved in the CSF - special value for treatment of meningitis and brain abscesses - crosses the placenta and secreted in breast milk - eliminated primarily by hepatic metabolism - monitoring of serum drug levels is frequently indicated 1.

Adverse Effects - gastrointestinal effects = vomiting, diarrhea, glossitis

- neurologic effects = peripheral neuropathy, optic neuritis, confusion, delirium - suprainfections of the bowel, allergic reactions and fever Gray Syndrome = commonly in infants, symptoms are vomiting, abdominal distention, cyanosis, and gray discoloration of the skin, followed by vasomotor collapse and death Reversible Bone Marrow Depression = dose-related depression of the bone marrow, resulting in anemia and sometimes leucopenia and thrombocytopenia - occurs most commonly when plasma drug levels exceed 25 mg/ml - cause appears to be inhibition of protein synthesis in host mitochondria - complete blood counts should be performed prior to therapy and every 2 days thereafter Aplastic Anemia = characterized by pancytopenia and bone marrow aplasia