The five general mechanisms comprise (1) inhibition of synthesis of cell wall, (2) damage to cell membrane, (3) modification of nucleic acid/DNA synthesis, (4) modification of protein synthesis (at ribosomes), and (5) modification of energy metabolism within the cytoplasm (at folate cycle).
Inhibitors of bacterial protein synthesis • Drugs that inhibit protein synthesis vary considerably in terms of chemical structures and their spectrum of antimicrobial activity. • Chloramphenicol, tetracyclines, and the aminoglycosides were the first inhibitors of bacterial protein synthesis to be discovered with broad spectrum of antimicrobial activity. • Erythromycin, an older macrolide antibiotic has a narrow spectrum of action. • Azithromycin and clarithromycin (semisynthetic macrolides), clindamycin and newer inhibitors developed lately as streptogramins, linozolid, telithromycin, and tigecycline have activity against certain bacteria that have developed resistance to older antibiotics.
I : Chloramphenicol • Chloramphenicol is a bacteriostatic antimicrobial that became available in 1949. it was isolated from cultures of streptomyces bacteria. • It inhibits bacterial protein by binding to the 50S ribosomal subunit. • Chloramphenicol is considered a prototypical broad spectrum antibiotic, is effective against a wide range of gram-positive and gram-negative bacteria, including most anaerobic organisms. • Because of its toxicity, its use is restricted to life-threatening infections for which no alternative exist. • Due to resistance and safety concerns, it is no longer a first-line agent for any infection.
Antibacterial spectrum • It is a bacteriostatic broad-spectrum antibiotic that is active against both aerobic and anaerobic gram positive and gram negative organisms • It is active not only against bacteria, but also against other microorganisms, such as Rickettsia. (A genus of gram-negative bacteria that are carried as parasites by many ticks, fleas, and lice and cause diseases such as typhus, scrub typhus, and Rocky Mountain spotted fever.) • It is bacteriostatic for most organisms but kills (bacterocidal) for Haemophilusinfluenzae, Neisseria meningitidisand Bordetella pertussis (Bacteroids). • It is not active against Klamedia species. • P. aeruginosais resistant to even very high concentrations of the drug. • Chlamydia is a genus of bacteria that are obligate intracellular parasites. • Chlamydia infections are the most common bacterial sexually transmitted infections in humans and are the leading cause of infectious blindness worldwide.[The three Chlamydiaspecies include Chlamydia trachomatis (a human pathogen), Chlamydia suis (affects only swine), and Chlamydia muridarum (affects only mice and hamsters).[
Classification and Pharmacokinetics • Chloramphenicol has a simple and distinctive structure, and no other antimicrobials have been discovered in this chemical class. • Chloramphenicol is extremely lipid soluble; it remains relatively unbound to protein and is a small molecule. • It has a large apparent volume of distribution, and penetrates effectively into all tissues of the body, including the brain. • The concentration achieved in brain and cerebrospinal fluid (CSF) is around 30 to 50%, even when the meninges are not inflamed; this increases to as high as 89% when the meninges are inflamed.
Pharmacokinetics • Chloramphenicol is effective orally as well as parenterally and is widely distributed readily crossing the placental and blood brain barriers. • Chloramphenicol undergoes enterohepatic cycling, and a small fraction of the dose (10%) is excreted in the urine unchanged. • Most of the drug is inactivated by a hepatic glucuronosyltransferase. • Chloramphenicol inhibits the hepatic mixed-function oxidases. • Chloramphenicol increases the absorption of iron
Clinical uses • Because of its toxicity, chloramphenicol has very few uses as a systemic drug. • Chloramphenicol should be reserved for serious infections in which benefit of the drug outweighs its uncommon but serious hematological toxicity, such uses may include: • Infections caused by H. influnzae resistant to other drugs. • Meningitis in patients whom penicillin cannot be used. • Chloramphenicol is active against the three main bacterial causes of meningitis: Neisseria meningitidis, Streptococcus pneumoniae and Haemophilus influenzae. • Chloramphenicol is sometimes used for rickettsial diseases. • The drug is commonly used as a topical antimicrobial agents in bacterial conjunctivitis. • It is effective in typhoid fever, but ciprofloxacin or amoxicillin and co-trimoxazole are similarly effective and less toxic.
Clinical use in special populations • Chloramphenicol is metabolized by the liver to chloramphenicol glucuronate (which is inactive). In liver impairment, the dose of chloramphenicol must therefore be reduced. • The majority of the chloramphenicol dose is excreted by the kidneys as the inactive metabolite, chloramphenicol glucuronate. Only a tiny fraction of the chloramphenicol is excreted by the kidneys unchanged. Plasma levels should be monitored in patients with renal impairment, but this is not mandatory. • Chloramphenicol succinate ester (the inactive intravenous form of the drug) is readily excreted unchanged by the kidneys, more so than chloramphenicol base, and this is the major reason why levels of chloramphenicol in the blood are much lower when given intravenously than orally. • Chloramphenicol passes into breast milk, so should therefore be avoided during breast feeding, if possible.
Adverse effects Aplastic anemia: • The most serious side effect of chloramphenicol treatment is aplastic anemia. This effect is rare and is generally fatal: there is no treatment and it is unpredictable. • Aplastic anemia is severe idiosyncratic depression of the bone marrow resulting in pancytopenia (a decreased in all blood cell elements) and independent of dose and may occur after therapy ceased. Bone marrow suppression: • Chloramphenicol commonly causes bone marrow suppression during treatment; this is a direct toxic effect of the drug on human mitochondria. This effect manifests first as a fall in hemoglobin levels. The anemia is dose-dependent and fully reversible once the drug is stopped. Leukemia • There is an increased risk of childhood leukemia, and the risk increases with length of treatment.
Adverse effects Gray baby syndrome • Intravenous chloramphenicol use has been associated with the so-called gray baby syndrome. • This phenomenon occurs in newborn infants because they do not yet have fully functional liver enzymes (i.e. UDP-glucuronyltransferase), so chloramphenicol remains unmetabolized in the body. This causes several adverse effects, including hypotension and cyanosis. The condition can be prevented by using the drug at the recommended doses, and monitoring blood levels. Gastrointestinal disturbances: • These conditions may occur from direct irritation and from superinfections, especially candidiasis (secondary to alteration of the intestinal microbial flora).
Drug interactions • Administration of chloramphenicol concomitantly with bone marrow depressant drugs is contraindicated. • Chloramphenicol is able to inhibit some of the hepatic mixed-function oxidases and, thus, blocks the metabolism of such drugs as: warfarin, phenytoin, tolbutamide, and chlorpropamide, thereby increasing their elimination half-life, elevating their concentrations and potentiating their effects. • 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.
II : Macrolides • The macrolide antibiotics are large cyclic lactone ring structures with attached sugars. • The main macrolide and related antibiotics are erythromycin, clarithromycin and azithromycin. • Erythromycin was the first of these drugs to be used clinically as drug of choice and as alternative to penicillin in individuals who are allergic to penicillin (mainly active against gram-positive organisms). • Clarithromycin and azithromycin are semisynthetic derivatives of erythromycin have greater gram-negative activity than erythromycin. • Telithromycin a semisynthetic derivative of erythromycin, is the first “ketolide” antimicrobial agent that has been approved. • The Ketolides are active against macrolide-resistant gram-positive strains.
Antimicrobial spectrum 1. Erythromycin: • This drug is effective against many of the same organisms as penicillin G, and is slightly wider than that of penicillin, it may be used in patients who are allergic to the penicillins. • Erythromycin is used to treat infections caused by Gram-positive bacteria (e.g. Streptococcus pneumoniae) and spirochaetes, but not against most gram-negative organisms, exceptions being N gonorrhoeae and, to a lesser extent, H influenzae. • Erythromycin has activity against many species of Campylobacter, Chlamydia, Mycoplasma, Legionella. • Erythromycin is not active against penicillin-resistant Streptococcus pneumoniae strains (PRSP) and MRSA strains.
2. Clarithromycin: • Clarithromycin is slightly more potent than erythromycin against sensitive strains of streptococci and staphylococci. • Clarithromycin is as active, and its metabolite is twice as active, against H. influnzae as erythromycin. • Its activity against intracellular pathogens, such as Chlamydia, Legionella, Moraxella, andUreaplasma species and Helicobacter pylori, is higher than that of erythromycin. 3. Azithromycin: • Azithromycin is far more active against respiratory infections due to H. influnzae and Moraxellacattarhalis. • Azithromycin is now the preferred therapy for urithritis caused by Chlamydia trachomatis, and for Mycobacterium infections. • It is also effective in gonorrhea, as an alternative to ceftriaxone and in syphilis, as an alternative to penicillin G.
4. Telithromycin: • This ketolide drug has an antibacterial spectrum similar of that of azithromycin. • The structural modification within ketolides neutralizes the most common resistance mechanisms (methylase-mediated and efflux-mediated) that make macrolides ineffective. • The drug can be used in community-acquired pneumonia including infections caused by multidrug-resistant organisms.
Pharmacokinetics Erythromycin: • The erythromycin base is destroyed by gastric acid. • Thus, enteric coated tablets or esterified forms of the antibiotic are administered. • All are adequately absorbed upon oral administration. • Intravenous administration of erythromycin is associated with a high incidence of thrombophlebitis. • It distributes well to all body fluids except the CSF. • it is extensively metabolized by the liver and is known to inhibit the oxidation with cytochrome P450 of several drugs for example: theophylline. • It is primarily concentrated and excreted in an active form in the bile. • Partial reabsorption occurs through the enterohepatic circulation. Inactive metabolites are excreted into the urine (15%).
Pharmacokinetics • Clarithromycin, azithromycin, and telithromycin are stable to stomach acid and readily absorbed. • Food interferes with the absorption of erythromycin and azithromycin, but can increase that of clarithromycin. • All these drugs are concentrate in the liver and are widely distributed in the tissues. • Inflammation allows for greater tissue penetration. • Azithromycin has the longest half-life and largest distribution. • Telithromycin inhibit cytochrome P450 system, and all are converted to active metabolites. • Clarithromycin and its metabolites (the active 14-hydroxy derivative metabolite) are eliminated by the kidneys as well as the liver.
Clinical uses • Erythromycin is effective in the treatment of infections caused by M pneumoniae, Corynebacterium, Bordetella pertussis, Ureaplasma urealyticum, and treponema pallidum. • Erythromycin is useful as a penicillin substitute in penicillin-allergic individuals with infections caused by streptococci or pneumococci. • Erythromycin or tetracycline is the drug of choice for Mycoplasmal pneumonia. • Erythromycin is an effective alternative for individuals who are allergic to penicillin for the prophylaxis of recurrences of rheumatic fever.
Clinical uses • Azithromycin has a similar spectrum of activity but is more active against Moraxella catarrhalis, Neisseria, H influnzae, and Legionella pneumophila. • Because of its long half-life, a single dose of azithromycin is effective in the treatment of urogenital infections caused by Chlamydia trachomatis. • Clarithromycin has almost the same spectrum of antimicrobial activity and clinical uses as erythromycin. • Clarithromycin 500 mg, in combination with omeprazole, 20 mg, and amoxicillin, 1 g, each administered twice daily for 10 to 14 days, is effective for treatment of peptic ulcer disease caused by H. pylori .
Adverse effects Gastrointestinal disturbance: • GIT disturbances are common and unpleasant but not serious. Anorexia, nausea, vomiting, and diarrhea occasionally accompany oral administration (due to a direct stimulation of gut motility). Cholestatic jaundice: • Cholestatic hepatitis is the most striking side effect (fever, jaundice, impaired liver function), probably as the result of a hypersensitivity reaction to the estolate form of erythromycin. Ototoxicity: Transient deafness has been associated with erythromycin, especially at high dosages. Allergic reactions: • Among the allergic reactions observed are fever, eosinophilia and skin eruptions, which may occur alone or in combination; each disappears shortly after therapy is stopped.
Inhibition of the cytochrome P450 system by erythromycin, clarithromycin, and telithromycin.
“Chancroid is a bacterial infection that is spread only through sexual contact
III : Aminoglycosides • Aminoglycoside antibiotics had been used for treatment of serious infections due to aerobic gram-negative bacilli. • Because their use is associated with serious toxicities, they have been replaced to some extent by safer antibiotics, such as the third- and fourth-generation cephalosporins, the fluoroquinolones, and the carbapenems. • Aminoglycosides that are derived from Streptomyces have -mycin suffixes, whereas those derived from micromonospora end in –micin. • The polycationic nature precludes their easy passage across tissue membranes. • All members of this family are believed to inhibit protein synthesis.
Aminoglycosides structure • The aminoglycoside are a group antibiotics of complex chemical structure composed of amino-modified sugars, resembling each other in antimicrobial activity, pharmacokinetic characteristics and toxicity. The main agents are gentamicin, streptomycin, amikacin, tobramycin, and neomycin.
Antibacterial spectrum • The aminoglycosides are effective against many aerobic gram-negative bacilli (including Peudomonasaeruginosa) and some gram-positive organisms. • They most widely used against gram-negative enteric organisms and sepsis.(Sepsis is an illness in which the body has a severe response to bacteria or other germs) • To achieve an additive or synergistic effect, aminoglycosides are often combined with a beta-lactam antibiotic, vancomycin, or a drug active against anaerobic bacteria. • They may be given together with a penicillin in streptococcal infections and those caused by Listeria spp. and P. aeruginosa. • Gentamicin and tobramycin commonly used for P. aeruginosa. • Amikacin has the widest antimicrobial spectrum and can be effective in infections with organisms resistant to gentamicin and tobramycin.
Pharmacokinetics • Aminoglycosides are polar compounds, not absorbed after oral administration and must be given intramuscularly, or intravenously for systemic effect. • Because aminoglycosides are concentration- and time-dependent and also have post antibiotic effect, once-daily dosing with the aminoglycosides can be employed. This results in less toxicity and less expensive to administer. • They have limited tissue penetration and do not pass the BBB. • Glomerular filtration is the major mode of excretion, 50-60% of a dose being excreted unchanged within 24 hr. • The plasma half-life (2-3 hr) of these drugs are greatly affected by changes in renal function. • If renal function is impaired, accumulation occurs rapidly, with resultant increase the dose related toxic effects (such as ototoxicity and nephrotoxicity).
Clinical uses • Gentamicin, tobramycin, and amikacin are important drugs for the treatment of serious infections caused by aerobic gram-negative bacteria, including E. coli and Enterobacter, Klebsiella, Proteus, Providencia, Pseudomonas, and Serratia species. • In most cases, aminoglycosides are used in combination with a beta-lactam antibiotic. Examples include their combined use with penicillins in the treatment of pseudomonal, listerial, and entercoccal infections. • Pseudomonalaeruginosa infections could be treated with tobramycin alone or in combination with piperacillin or ticarcillin. • Enterococci infections could be treated with gentamicin or streptomycin plus vancomycin or ampicillin. • Gentamicin is the drug of choice for the treatment of tularemia. (Tularemia is usually a disease of animals. Humans can acquire tularemia when they come in contact with infected animals or are bitten by insects that have fed on an infected animal.)
Clinical uses • Streptomycin in combination with penicillins is used in the treatment of enterococcalcarditis, tuberculosis, and plague. • Because of the risk of ototoxicity, streptomycin should not be used when other drugs well serve. • Owing to their toxic potential, neomycin and kanamycin are usually restricted to topical (for the conjunctiva or external ear) or oral use (e.g., eliminate bowel flora). Gentamicin is also available for topical use. • Because of their toxicity with prolonged administration, aminoglycosides should not be used for more than a few days unless deemed essential for a successful or improved outcome. • Once the microorganism is isolated and its sensitivities to antibiotics are determined, the aminoglycoside should be discontinued if the infecting microorganism is sensitive to less toxic antibiotics.
Side effects Serious, dose-related toxic effects, which may increase as treatment proceeds, can occur with the aminoglycosides. The main hazards being ototoxicity and nephrotoxicity. 1. Ototoxicity: • Its directly related to high peak plasma levels and the duration of treatment. Auditory or vestibular damage (or both) may occur with any aminoglycoside and may be irreversible. • Auditory impairment or deafness is more likely with neomycin, amikacin and kanamycin while vestibular dysfunction manifested as vertigo, ataxia, and loss of balance is more likely with streptomycin, gentamicin and tobramycin. • Ototoxicity may be increased by the use of other ototoxic drugs (e,g., loop diuretics, cisplatin, etc.).
In the case of the auditory part of CN VIII, the symptoms are deafness or tinnitus (ringing in the ears). In the case of the vestibular part of CN VIII, the symptoms are vertigo or imbalance.
Side effects 2. Nephrotoxicity: • Renal toxicity usually takes the form of acute tubular necrosis. Its reversible and more common in elderly patients and in those taking nephrotoxic agents (e.g., 1st generation cephalosporins, vancomycin). Gentamicin and tobramycin are the most nephrotoxic. 3. Neuromuscular blockade: • Paralysis caused by neuromuscular blockade may occur at high doses of aminoglycoside. It results from inhibition of calcium uptake. Patients with myasthenia gravis are at risk. 4. Skin reactions: • Allergic skin reactions may occur in patients, and contact dermatitis may occur in personnel handling the drug. Neomycin is the agent most likely to cause this adverse effect.
Tetracycline antibiotics • Tetracyclines are a group of broad-spectrum bacteriostatic antibiotics that inhibit protein synthesis. • The group includes tetracycline, doxycycline and minocycline. They have only minor differences in their activities against specific organisms. • Their general usefulness has been reduced with the onset of bacterial resistance. Despite this, they remain the treatment of choice for some specific indications. • They are so named for their four (“tetra-”) hydrocarbon rings (“-cycl-”).
Classification • All of the tetracycline have the basic structure shown below:
Tetracycline bind to the 30S ribosomal subunits, thus preventing the binding of aminoacyl-tRNA to the ribosome. Mechanism of action
Antibacterial spectrum • As broad spectrum bacteriostatic antibiotics, the tetracyclines are effective against gram-positive and gram-negative bacteria, as well as organisms other than bacteria such as: Mycoplasma, Rickettsia, Chlamydia spp., spirochetes, and some protozoa (e.g., amoebae). • Minocycline is also effective against N. meningitidis. • The antibacterial activities of most tetracyclines are similar except that tetracycline-resistant strains may remain susceptible to doxycycline or minocycline.
Pharmacokinetics • The tetracyclines are generally given orally but can also be administered parenterally. • Minocycline and doxycycline are lipid soluble and virtually completely absorbed. • The absorption of most other tetracyclines is irregular and incomplete but is improved in the absence of food. • Because tetracyclines chelate metal ions (calcium, magnesium, iron, aluminum), forming non-absorbable complexes, absorption is decreased in the presence of milk, certain antacids and iron preparations. • A portion of an orally administered dose of tetracycline remains in the gut lumen, modifies intestinal flora, and is excreted in the feces. • Minocycline and doxycycline are long acting tetracycline while tetracycline is short acting.