1. PHL 424 Antimicrobials
7th Lecture By Abdelkader Ashour, Ph.D. Phone:

2. Inhibitors of bacterial protein synthesis, Chloramphenicol, contd.
Therapeutic Uses:
Because of potential toxicity, bacterial resistance, and the availability of other effective drugs (e.g., cephalosporins), chloramphenicol is almost an obsolete as a systemic drug
It may be considered for treatment of serious rickettsial infections in children for whom tetracyclines are contraindicated, i.e., those under 8 years of age
It is an alternative to b-lactam antibiotics for treatment of meningococcal meningitis occurring in patients who have major hypersensitivity reactions to penicillin or bacterial meningitis caused by penicillin-resistant strains of pneumococci
It is used topically in the treatment of eye infections because of its wide antibacterial spectrum and its penetration of ocular tissues and the aqueous humor

3. Inhibitors of bacterial protein synthesis, Chloramphenicol, contd.
Side effects:
The most important adverse effect of chloramphenicol is on the bone marrow
It affects the hematopoietic system in two ways: a dose-related toxicity that presents as anemia, leukopenia, or thrombocytopenia; and an idiosyncratic response manifested by aplastic anemia, leading in many cases to fatal pancytopenia
A genetic predisposition is suggested by the occurrence of pancytopenia in identical twins
Aplastic anemia accounts for approximately 70% of cases of blood dyscrasias due to chloramphenicol, while hypoplastic anemia, agranulocytosis, and thrombocytopenia make up the remainder
Dose-related, reversible erythroid suppression due to an inhibitory action of chloramphenicol on mitochondrial protein synthesis in erythroid precursors, which in turn impairs iron incorporation into heme
Nausea and vomiting, unpleasant taste, diarrhea, and perineal irritation may follow the oral administration of chloramphenicol
Oral or vaginal candidiasis may occur as a result of alteration of normal microbial flora

4. Inhibitors of bacterial protein synthesis, Chloramphenicol, contd.
Side effects, cont.d
Toxicity for Newborn Infants
Newborn infants, especially if premature, lack an effective glucuronic acid conjugation mechanism for the degradation & detoxification of chloramphenicol, with subsequent inadequate renal excretion of unconjugated drug
Consequently, when infants are given dosages above 50 mg/kg/d, the drug may accumulate, resulting in a serious illness termed gray baby syndrome, with vomiting, refusal to suck, passage of loose, green stools, cyanosis, ashen-gray color, flaccidity, hypothermia, shock and collapse
Death occurs in about 40% of patients within 2 days of initial symptoms. Those who recover usually exhibit no sequelae
To avoid this toxic effect, chloramphenicol should be used with caution in infants, and the dosage limited to 50 mg/kg/d or less (during the first week of life) in full- term infants and 25 mg/kg/d in premature infants
Toxic effects have not been observed in the newborns when as much as 1 g of the antibiotic has been given every 2 hours to the mothers during labor

5. Inhibitors of bacterial protein synthesis, Chloramphenicol, contd.
Drug interactions:
It inhibits hepatic microsomal enzymes that metabolize several drugs such as warfarin
Conversely, other drugs may alter the drug elimination. Concurrent administration of phenobarbital or rifampin, which potently induce CYPs, shortens its t1/2 and may result in subtherapeutic drug concentrations
Like other bacteriostatic inhibitors of microbial protein synthesis, chloramphenicol can antagonize bactericidal drugs such as penicillins or aminoglycosides

6. Inhibitors of bacterial protein synthesis, Tetracyclines
Tetracyclines are broad-spectrum bacteriostatic antibiotics that inhibit protein synthesis
Oxytetracycline is a natural product produced by Streptomyces rimosus. Tetracycline is a semisynthetic derivative of chlortetracycline, produced by Streptomyces aureofaciens
Demeclocycline is the product of a mutant strain of Strep. Aureofaciens
Methacycline, doxycycline and minocycline all are semisynthetic derivatives

7. Inhibitors of bacterial protein synthesis, Tetracyclines, contd.
MOA:
Tetracyclines enter microorganisms in part by passive diffusion and in part by an energy-dependent process of active transport
Tetracyclines then bind reversibly to the 30S subunit of the bacterial ribosome, blocking the binding of aminoacyl-tRNA to the acceptor site on the mRNA-ribosome complex
This prevents addition of amino acids to the growing peptide

8. Inhibitors of bacterial protein synthesis, Tetracyclines, contd.
Antimicrobial actions:
Tetracyclines are active against many G+ve & G-ve bacteria, including anaerobes, rickettsiae, chlamydiae, mycoplasmas
They are also active against some protozoa, e.g., amebas
The antibacterial activities of most tetracyclines are similar except that tetracycline-resistant strains may remain susceptible to doxycycline or minocycline, drugs that are less rapidly transported by the pump that is responsible for resistance
Resistance mechanisms :
Decreased intracellular accumulation due to either decreased influx or increased efflux by an active transport protein pump … (the most important)
Ribosome protection due to production of proteins that interfere with tetracycline binding to the ribosome
Enzymatic inactivation of tetracyclines
Resistance is primarily plasmid-mediated and often is inducible

9. Inhibitors of bacterial protein synthesis, Tetracyclines, contd.
Pharmacokinetics
Tetracyclines mainly differ in their absorption after oral administration and their elimination
Absorption after oral administration is approximately 30% for chlortetracycline; 60– 70% for tetracycline, oxytetracycline, demeclocycline, and methacycline; and 95– 100% for doxycycline and minocycline
A portion of an orally administered dose of tetracycline remains in the gut lumen, modifies intestinal flora, and is excreted in the feces
Absorption occurs mainly in the upper small intestine and is impaired by food (except doxycycline and minocycline); by divalent cations (Ca2+, Mg2+, Fe2+) or Al3+; by dairy products and antacids, which contain multivalent cations, …..so!
The decreased absorption results from chelation of divalent and trivalent cations
Tetracyclines are 40–80% bound by plasma proteins. They are distributed widely to tissues and body fluids except for CSF (levels are 10–25% of those in serum)
Tetracyclines cross the placenta to reach the fetus and are also excreted in milk. As a result of chelation with calcium, tetracyclines are bound to—and damage—growing bones and teeth

10. Inhibitors of bacterial protein synthesis, Tetracyclines, contd.
Pharmacokinetics, contd.
Tetracyclines are excreted mainly in urine and bile. Some of the drug excreted in bile is reabsorbed from the intestine (enterohepatic circulation) and contributes to maintenance of serum levels
Doxycycline, in contrast to other tetracyclines, is eliminated by nonrenal mechanisms (excreted in feces), does not accumulate significantly in renal failure, and requires no dosage adjustment, making it the tetracycline of choice for use in the setting of renal insufficiency
Minocycline is recovered from urine and feces in significantly lower amounts than are the other tetracyclines, and it appears to be metabolized to a considerable extent Its renal clearance is low. The drug persists in the body long after its administration is stopped, possibly due to retention in fatty tissues. Nonetheless, its half-life is not prolonged in patients with hepatic failure

11. Inhibitors of bacterial protein synthesis, Tetracyclines, contd.
Therapeutic Uses:
A tetracycline is the drug of choice in infections with Mycoplasma pneumoniae, chlamydiae (e.g., C. trachomatis ) and rickettsiae (e.g., Rocky Mountain spotted fever)
They may be employed in various G+ve and G-ve bacterial infections, including vibrio cholera infections, provided the organism is not resistant
Tetracyclines are used in combination regimens to treat gastric and duodenal ulcer disease caused by Helicobacter pylori
A tetracycline—usually in combination with an aminoglycoside—is indicated for plague and brucellosis
Tetracyclines are sometimes employed in the treatment of protozoal infections, e.g., those due to Entamoeba histolytica or Plasmodium falciparum
Tetracyclines have been used to treat acne. They may act by inhibiting propionibacteria, which reside in sebaceous follicles and metabolize lipids into irritating free fatty acids. The relatively low doses of tetracyclines used for acne are associated with few side effects