Antibacterial Drugs: Tetracycline and Amphenicols

How do bacteria resist the effects of tetracyclines?

1. Decrease drug concentration in bacteria (due to decreased drug penetration or increased efflux) 2. Protect target (30S ribosomal RNA) from drug binding--due to expression of ribosome protection proteins (6 classes) 3. Enzymatic inactivation of drug molecule (rare)

Antimicrobial activity of amphenicols

Active against most aerobic and anaerobic Gram (+) and (-) bacteria and several atypicals, incl. Mycoplasma, Chlamydia and Rickettsia. Resistant organisms include Nocardia and Mycobacteria.

Antimicrobial activity of tetracyclines

Bacteriostatic action against many aerobic and anaerobic Gram (+) and Gram (-) bacteria. Good activity against several atypical and tick-borne bacteria such as Rickettsia, Borrelia, Ehrlichia and Anaplasma. Tetracyclines also have activity against several protozoöans, incl. Giardia and Toxoplasma. Newer tetracycline analogs have activity against some tetracycline-resistant bacteria

Adverse effects of amphenicols

Bone marrow depression with overdose or prolonged treatment in most species. Due to decreased protein synthesis in erythroid cells (can produce dose- dependent anemia). Reversible effect. Gastrointestinal disturbances (e.g. diarrhea) reported in cats, dogs, calves Hypotension after i.v. injection to calves

Adverse effects of tetracyclines

Gastrointestinal disturbances Nausea, vomiting in some species (irritation) Superinfections leading to colitis in horses, due to negative impact on commensal gut flora Bone and tooth discoloration in young animals Deposition of Ca2+-tetracycline complexes in active ossification sites and growing teeth.

Absorption and distribution of amphenicols

Good p.o. bioavailability in monogastrates and pre-ruminant animals. Inactivated in ruminal fluids, so florfenicol is usually given i.m. to livestock. Large Vd, with low to moderate plasma protein binding. Tissue concentrations often similar to plasma concentrations. Distributes into hard to access areas (ocular fluids, CSF, etc)

Tetracyclines in companion animals

Doxycycline is used to treat some upper respiratory tract infections and bacterial conjunctivitis. Doxycycline or other tetracyclines are also indicated for Lyme disease (Borrelia), brucellosis, ehrlichiosis, leptospirosis, and chlamydial and Rickettsial infections.

Use of amphenicols in companion animals

Empirical treatment of serious anaerobic infections, e.g. penicillin-resistant Bacteroides infections, CNS infections Mixed infections involving anaerobes, e.g. aspiration pneumonia - oral anaerobes; provides broad-spectrum coverage; better than penicillins and lincosamides. Serious infections involving Gram (+) cocci or Gram (-) bacilli, e.g. systemic salmonellosis; deep eye infections caused by Gram (+) bacteria and anaerobes. Second or third line treatment of prostatic infections in dogs caused by Gram (-) organisms

Public health concerns related to tetracyclines

Extensive use, high prevalence of multi-drug resistant coliform organisms Resistance in many clinical isolates of E coli, Salmonella, Staph, Pseudomonas, Klebsiella, Pasteurella

Difference between florfenicol and chloramphenicol

Florfenicol is more potent than chloramphenicol and in some cases, has bactericidal activity vs. sensitive organisms.

absorption and distribution of tetracyclines

Good p.o. bioavailability. Large Vd . Lipid-soluble tetracyclines (e.g. doxycycline) penetrate blood-brain barrier, bone and prostate. Lipid-soluble tetracyclines bind more extensively to plasma proteins than water-soluble tetracyclines.

Who can't have chloramphenicol?

In people, chloramphenicol treatment was associated with development of idiosyncratic aplastic anemia and the drug is banned from use in food animals. HUMANS AVOID CONTACT.

Tetracyclines in ruminants and swine

Many approved uses for short-acting drugs (chlortetracycline or oxytetracycline) in treating topical, organ system and systemic infections involving susceptible microbes, e.g. neonatal scours, respiratory infections, keratoconjunctivitis, leptospirosis. OBSERVE WITHDRAWAL TIMES!

Metabolism and excretion of tetracyclines

Metabolism. Enterohepatic recycling with few metabolites. Recycling contributes to drug persistence (like long doxycycline t1⁄2) ◦ Chlortetracycline has relatively short t1⁄2 because it breaks down in alkaline environments. Excretion. Most tetracyclines are excreted unchanged in urine and bile with some excretion into milk.

What limits the absorption of tetracyclines?

Milk and other Ca2+-containing foods limit drug absorption.

Can any amphenicols be used in food animals?

Newer amphenicols (e.g. florfenicol) produce no bone marrow depression and are used in pigs and cattle.

Tetracyclines in horses

Oxytetracycline is used to treat ehrlichiosis, Potomac Horse fever (Neorickettsia risticii), mycoplasma-assoc. lower respiratory infections and infections by some atypical bacteria. Oral doxycycline can be given as an alternate therapy; i.v. injection produces adverse cardiovascular effects and even death.

Metabolism and excretion of amphenicols

Phase 1 and/or Phase 2 metabolism. At least 50% of florfenicol is excreted unchanged in urine. Drug interactions!-->chloramphenicol inhibits hepatic CYP450 enzymes. Excretion: renal > biliary excretion

Which organisms are resistant to tetracyclines?

Pseudomonas and Proteus spp. Some Mycoplasma Resistance is widespread in enteric bacteria (Enterobacteriaceae) and mycobacteria, but less common in many intracellular bacteria, e.g. Anaplasma. Usually plasmid-mediated; R-plasmids are carried by transposons.

What do amphenicols target?

Reversibly bind to the 50S ribosome, stops the addition of amino acids to growing protein chains. The ribosomal binding of amphenicols can be blocked by macrolide, lincosamide, and streptogramin (MLS) antibacterial drugs, which bind to adjacent sites in the 50S ribosome.

Tetracyclines and birds

Short-acting tetracyclines are the most widely used antimicrobial drugs in poultry. Treatment of respiratory, joint and intestinal infections, e.g. chronic respiratory disease (Mycoplasma), fowl cholera (Pasteurella), infectious synovitis (Mycoplasma).

How do tetracyclines form precipitates?

Tetracyclines chelate Ca2+ and other divalent cations to form precipitates.

Tetracycline mechanism of action

Tetracyclines reversibly bind to the 30S ribosome and stop the addition of amino acids to the growing peptide chain that forms proteins.

How does selective toxicity work with tetracycline?

The antibacterial selectivity of tetracycline action is due to the preferential accumulation of these drugs into prokaryotic cells (thanks to bacterial active transport!)

Bacterial resistance to amphenicols

Usually plasmid-mediated, often carried on transposons with other drug resistance genes Mechanisms: Chloramphenicol can be chemically inactivated by bacterial enzymes. Expression of bacterial efflux pumps for all amphenicols.

2 types of tetracyclines

Water-soluble, short-acting: chlortetracycline, oxytetracycline Lipid-soluble, long-acting: doxycycline

Are tetracyclines bacteriostatic or bactericidal?

bacteriostatic

Florphenicol in food animals

respiratory infections in pigs and calves; usually tried after other drug classes (fluoroquinolones, macrolides, tetracyclines).

Amphenicols are very good for ________ infections.

serious

Are amphenicols bacteriostatic or bactericidal?

static

Are amphenicols time or concentration dependent?

time

Is tetracycline time or concentration dependent?

time

What do tetracyclines and amphenicols have in common?

• Both classes of drugs interfere with bacterial ribosomes to arrest protein synthesis in bacteria. • Both classes have intermediate to broad spectrum bacteriostatic effects. • These drugs are mainly used for respiratory and niche infections.