Antimicrobial Agents II
Chemotherapeutics are antimicrobial agents that are used for germs killing inside the organism; the antimicrobial action usually occurs after they’re appearing in system blood circulation.
Spectrum activity of agent is the list of microorganisms, that are sensitive to him. Chemotherapeutic spectrum is the list of infectious diseases, which can be cured by this agent.
The principles of effective chemotherapeutic actions are the following:
1. Rational choice of preparation according to clinical and bacteriologic diagnosis.
2. Optimal dosage, way and interval between drug using.
3. Beginning of therapy as soon as possible before destructive changes of organs.
4. If the clinical improvements after 2-3 days course are absent, the agent must be changed.
5. The therapy have been continued 2-3 days after the clinical symptoms disappear.
6. Chemotherapy should be performed with other remedies that enforce the immunity.
Antibiotics are the products of certain mycotic organisms, different bacteria. With the help of antibiotics these microorganisms can suppress the growing of another microbes or kill them. Antibiotic, which formed by alive organism, is biosynthetic (natural) antibiotic, however after chemical conversions it becomes semisynthetic antibiotic. Finally, antibiotic that we get as result of chemical reaction only named as synthetic antibiotic.
In 1929 Alexander Fleming reported his discovery of first antibiotic - penicillin. In 1940 Chain, Florey succeeded in producing significant quantities of the first penicillin and discovered its efficiency for infectious disease. Ermolyeva during World War II elaborated the commercial production of penicillin in the USSR. Vaksman made educing of streptomycin in 1944.
Classification of antibiotics on a spectrum of their antimicrobial activity.
I. With the main influence on the gram-positive microbes: penicillins; cephalosporins; macrolides; reserve antibiotics (lincomycin, vancomycin).
II. With main influence on the gram-negative microbes: aminoglycosides.
III. Influencing both gram-positive and negative microbes: tetracyclines; levomycetin (chloramphenicol).
IV. Influencing both gram-positive and negative microbes, and used locally: polymyxins; neomycin; monomycin; gramicidine.
V. Antifungal antibiotics: nystatin; griseofulvin; amphotericin B.
VI. Anticancer preparations: actinomycin, olivomycin, bruneomycin.
Classification under the mechanism of action:
1. Antibiotics that inhibit bacterial microbe’s cell wall synthesis: penicillins, cephalosporins, and vancomycin.
2. Antibiotics disordering permeability of microbe’s cell capsule (decreasing the surface straining or detergent effect): antifungal antibiotics, polymyxins.
3. Antibiotics inhibiting synthesis of DNA, RNA: griseofulvin, rifampicin, and anticancer antibiotics.
4. Antibiotics inhibiting the protein synthesis of the microorganisms: macrolides, aminoglycosides, tetracyclines, and levomycetin.
Antibiotics can act bactericidal (penicillins, cephalosporins, aminoglycosides, polymyxins) and bacteriostatic (macrolides, tetracyclines, levomycetin, antimycotic antibiotics). Also antibiotics divided into basic (main) agents and supplemental (reserve) agents. Usually, reserve antibiotics are less effective and more toxic, than basic agents are. Thus, the reserve antibiotics are indicated only in case of resistance or hypersensitivity to basic antibiotics.
When the inhibitory or killing effects of two or more antimicrobials used together are significantly greater than expected from their effects when used individually, synergism is said to result. For example, benzylpenicillin in combination with gentamicin is superior to monotherapy with a penicillin or gentamicin for the treatment of enterococcal endocarditis. Enzymatic inactivation of β-lactam antibiotics is a major mechanism of antibiotic resistance. Several β-lactam+β-lactamase inhibitor combinations (e.g., amoxicillin-clavulanic acid) have been successful against a variety of bacterial infections.
On the other hand, bacteriostatic agents such as tetracyclines and levomycetin can antagonize the action of bactericidal cell wall-active agents (e.g., β-lactam antibiotics). The bactericidal effects of cell wallactive agents require that the bacteria be actively growing and dividing. This antagonistic interaction is thought to be due to inhibition of bacterial growth by the bacteriostatic agent. Tetracyclines and levomycetin have also been shown to antagonize the bactericidal effects of aminoglycosides. Also it is not recommended the concurrent using of agents with the similar adverse effect, e.g., aminoglycosides with polymyxins.
In spite of the specific activity of antibiotics, they may cause some adverse effects. There are the following adverse effects, characteristic for antibiotics:
1. Allergic reactions of immediate and delayed types. Anaphylactic shock, angioneurotic laryngeal edema, exfoliative dermatitis, bullous erythema are the most hazardous. They are often caused by penicillins, cephalosporins.
2. Dysbacteriosis is the modification of normal gastro-intestinal microflora, with suppression of susceptible coliform organisms. It leads to superinfection - overgrowing of Pseudomonas, Proteus, staphylococci, clostridia, and Candida. This can result in intestinal functional disturbances, anal pruritus, vaginal or oral candidiasis, staphylococcus enteritis, and hypovitaminosis. Antibiotics with a wide efficiency spectrum (tetracyclines, levomycetin, and ampicillin) usually cause such effect.
3. Toxic reactions that are specific for antibiotics and depend on the dose and therapy terms. For example, levomycetin causes bone marrow depression: reticulocytopenia, anemia, and granulocytopenia. Aminoglycozides are neurotoxic (neuritis of vestibulocochlear nerve); aminoglycozides and polymyxins can cause nephrotoxic impairments while tetracyclines are hepatotoxic.
4. Endotoxic reaction that is usually appears at the beginning of specific treatment of syphilis, typhoid fever, and meningitis. It may cause a state of shock, accompanied by severe diarrhea, fever, and leukopenia followed by leukocytosis. The reason of endotoxic reaction is releasing of endotoxin, which form an integral part of the cell wall of a variety of Gram-negative bacteria.
The β-lactam antibiotics are the most frequently used group of antibiotics. The β-lactam compounds are penicillins, cephalosporins, monobactams, carbapenems, and beta-lactamase inhibitors.
Penicillin is produced by different species of Penicillium cultures. It inhibit bacterial microbes cell wall synthesis. Penicillins are bactericidal agents. All penicillins are the derivatives of 6-aminopenicillanic acid, which consists of thiazolidine ring and β-lactam ring. If the beta-lactam ring is enzymatically cleaved by bacterial beta-lactamases, the resulting product, penicilloic acid lacks antibacterial activity.
1. Biosynthetic penicillins: benzylpenicillin sodium, potassium or novocaine salts (penicillin G); phenoxymethylpenicillin (penicillin V); bicillin-1 (penicillinG benzathine); bicillin-5.
2. Semisynthetic penicillins:
a) penicillinase resistant agents: oxacillin; methicillin; nafcillin
b) extended-spectrum penicillins: ampicillin, amoxicillin and antipseudomonal penicillins: carbenicillin, carfecillin, azlocillin.
The spectrums of activity of biosynthetic penicillins include gram-positive cocci (stapylo-; pneumo- and streptococci), gram-negative cocci (meningo- and gonococcus), anaerobes (Clostridium tetani, Cl. perfringens). Some other organisms for which biosynthetic penicillin has good activity include Bacillus anthracis, Corynebacterium diphtheriae, and Treponema pallidum. However, many strains of staphylococci produce beta-lactamases, which destroy these penicillins.
Benzylpenicillin sodium and potassium are not absorbed from gastro-intestinal tract, because they are destroyed in acidic medium of stomach. After i.m. injection peak of blood concentrations are usually obtained within 30 minutes and stay during 3-4 hours. For maintenance of blood stable concentration it must be administrated every 4 hours. Benzylpenicillins are widely distributed to most tissues and body fluids. They also cross the placenta and are distributed into breast milk. Distribution into the cerebrospinal fluid is low in subjects with noninflamed meninges, as is penetration into purulent bronchial secretions.
The normal half-life of benzylpenicillin sodium and potassium is approximately 30 minutes. Hepatic metabolism accounts for less than 30% of the biotransformation of benzylpenicillins. They are rapidly excreted by the kidneys into the urine. About 10% of renal excretion is by glomerular filtration and 90% by tubular secretion. Blood levels of all penicillins can be raised by simultaneous administration of probenecid, which impairs their tubular secretion.
Benzylpenicillin sodium and potassium are the drug of choice for the treatment of actinomycosis, anthrax, diphtheria, gonorrhea, scarlet fever, syphilis, and gas gangrene. They also are used in the treatment of bacterial endocarditis, bacterial septicemia, sore throat, acute otitis media, bacterial pneumonia, rheumatic fever, bone and joint infections, skin diseases caused by susceptible organisms.
Benzylpenicillin novocaine is dissolves slowly at the site of injection, maintaining therapeutic concentration during 8-12 hours. It has been used 3-4 times a day intramuscularly. It has the same spectrum antimicrobial activity, as benzylpenicillin sodium or potassium salts. On the other hand, benzylpenicillin novocaine contains novocaine, which increase the danger of allergic reactions.
Bicillin-1 and bicillin-5 are slowly released from the i.m. injection site and hydrolyzed to benzylpenicillin, resulting in serum concentrations that are much lower but much more prolonged than other parenteral penicillins. A single injection of bicillin-1 or bicillin-5 intramuscularly once every 2-4 weeks is satisfactory for the treatment of syphilis, and for prophylaxis or treatment of rheumatic fever.
Phenoxymethylpenicillin is acid-resistant. It is indicated only in minor infections: prophylaxis of diphtheria and rheumatic fever, treatment of scarlet fever and sore throat. It is presribed four times a day.
Oxacillin is resistant to staphylococcal penicillinase (β-lactamase). The sole indication for the use of this agent is infection by penicillinase-producing staphylococci; however, it is less potent than benzylpenicillin against penicillin-sensitive bacteria. Oxacillin is acid-stable and reasonably well absorbed from the gut. It is widely distributed to most tissues and body fluids. It is ingested four times a day. For serious systemic staphylococcal infections, oxacillin is given by intermittent intravenous infusion of 1-2 g every 4-6 hours. Methicillin is no longer used because of its nephrotoxicity.
Ampicillin, amoxicillin are extended-spectrum penicillins. These drugs retain the antibacterial spectrum of penicillin, differ in having greater activity against gram-negative cocci and bacteria such as Escherichia coli, Shigella, and Salmonella species. Like benzylpenicillin, they are inactivated by penicillinase.
Ampicillin and amoxicillin are acid-stable and relatively well absorbed, achieving serum concentrations within 1-2 hours (for intramuscularly injection – 0,5 hour). Amoxicillin is better absorbed from the gut, than ampicillin. The duration of action is about 4-6 hours. Ampicillin is excreted in the bile in high concentrations. Amoxicillin is only oral penicillins, than can be taken during mealtimes, all another oral penicillins should be given 1-2 hours before or after eating to minimize binding to food proteins and acid inactivation. Ampicillin and amoxicillin can be used for the treatment bone and joint infections, sore throat, bronchitis, pneumonia, meningitis, bacillary dysentery, typhoid fever, septicemia, urinary tract infections caused by susceptible organisms.
Ampicillin, amoxicillin are also available in combination with one of several beta-lactamase inhibitors: clavulanic acid, sulbactam. The addition of a beta-lactamase inhibitor extends the activity of these penicillins to include beta-lactamase-producing strains of staphylococci as well as some beta-lactamase-producing gram-negative bacteria. For example, Unasyn (ampicillin+sulbactam), Aygmentin (amoxicillin+ clavulanic acid).
Ampiox is the combination of ampicillin and oxacillin. Thanks to that it active against both penicillinase-producing staphylococci and broad spectrum of gram-positive and gram-negative microbes.
The antipseudomonal penicillins (carbenicillin, carfecillin, and azlocillin) are also extended-spectrum penicillins, but they have less activity against gram-positive organisms than the natural penicillins or ampicillin; however, unlike the other penicillins, these penicillins are active against some gram-negative bacilli, including Pseudomonas aeruginosa, Proteus vulgaris. Carbenicillin is the first antipseudomonal carboxypenicillin. Carfecillin is the converted carbenicillin; it can be used orally. It active in lower doses, than carbenicillin. The ureidopenicillins, azlocillin, resemble carbenicillin except that it is also active against selected gram-negative bacilli, such as Klebsiella pneumoniae, and more potent against Pseudomonas aeruginosa, than carbenicillin.
Carbenicillin, carfecillin, and azlocillin are indicated in the treatment of bone, joint, skin, and soft tissue infections, endocarditis, septicemia, pneumonia, meningitis, intra-abdominal infections, prostatitis, female pelvic infections, and urinary tract infections caused by susceptible organisms.
Adverse effects. The penicillins are remarkably nontoxic. Most of the serious adverse effects are due to hypersensitivity. It’s appearing quite frequent 1-10%. All penicillins are cross-sensitizing and cross-reacting. Allergic reactions include fever, joint swelling, angioneurotic edema, pruritus, and rashes. Very rare anaphylactic shock may occur. In patients with renal failure, penicillins in high doses can cause seizures. Large doses of penicillins given orally may lead to gastrointestinal upset, particularly nausea, vomiting, and diarrhea. Ampicillin has been associated with pseudomembranous colitis. Secondary infections such as vaginal candidiasis may occur. Ampicillin and amoxicillin can cause skin rashes that are not allergic in nature.
First cephalosporin was obtained from culture of Cephalosporinum acremonium. Cephalosporins are similar to penicillins chemically, in mechanism of action, and toxicity. Cephalosporins are more stable than penicillins to many bacterial β-lactamases and therefore usually have a broader spectrum of activity. The nucleus of the cephalosporins is 7-aminocephalosporanic acid. Cephalosporins can be classified into four major groups or "generations," depending mainly on the spectrum of antimicrobial activity. As a general rule, first-generation compounds have better activity against gram-positive organisms and the later compounds exhibit improved activity against gram-negative aerobic organisms.
First-generation cephalosporins: cefazolin, cephalothin, cephaloridine, cephalexin.
Second-generation cephalosporins: cefaclor, cefuroxime, cefoxitin.
Third-generation cephalosporins: cefotaxime, ceftriaxone, cefixime.
Fourth-generation cephalosporins: cefepime, cefpirome.
First-generation cephalosporins are active against gram-positive cocci (pneumo-, strepto-, and staphylococci), Neisseria gonorrhoeae, Escherichia coli, Klebsiella pneumoniae, and Proteus mirabilis. They are used to treat septicemia, bone and joint infections, otitis media, pneumonia, skin and soft tissue infections, including burn wound infections, and urinary tract infections caused by susceptible bacterial organisms. These medications are possible alternatives to the penicillins for staphylococcal and streptococcal infections.
Cefazolin can be used intramuscularly or intravenously every 8 hours (see table 3.1). Excretion is via the kidney. Cefazolin penetrates well into most tissues. It is the drug of choice for surgical prophylaxis because of its longer half-life. Cefazolin may be a choice in infections for which it is the least toxic drug (e.g., Klebsiella pneumoniae). Cephalexin is absorbed from the gut to a variable extent. Urine concentration is usually very high. It may be used for the treatment of urinary tract infections, for minor staphylococcal lesions, or for minor polymicrobial infections such as cellulitis or soft tissue abscess.
In general, second-generation cephalosporins are active against organisms affected by first-generation drugs, but they have an extended gram-negative coverage, e.g., Proteus vulgaris, Enterobacter, Haemophilus influenzae. All second-generation cephalosporins are less active against gram-positive bacteria than the first-generation drugs. Some Enterobacter species can express a chromosomal beta-lactamase that hydrolyzes second-generation cephalosporins (as well as third-generation cephalosporins).
Cefuroxime is the only second-generation drug that crosses the blood-brain barrier, but it is less effective in treatment of meningitis than ceftriaxone or cefotaxime and should not be used. However, cefuroxime more stable against certain β-lactamases. Cefuroxime is commonly used to treat community-acquired pneumonia because of its extend spectrum activity. Cefuroxime axetil, an oral prodrug of cefuroxime, is hydrolyzed to cefuroxime after absorption. It has been used to treat mild to moderate bronchitis, otitis media, skin and soft tissue infections, uncomplicated gonococcal urethritis, and urinary tract infections.
Cefoxitin has the greatest stability in the presence of β-lactamases produced by the Bacteroides fragilis group. Because of its activity against anaerobes, cefoxitin can be useful in such mixed anaerobic infections as aspiration pneumonia, intra-abdominal and female pelvic infections. It is also used prophylactically to help prevent perioperative infections that may result from colorectal surgery and appendectomies, and in the treatment of penicillin-resistant strains of gonorrhea.
Cefaclor is more susceptible to β-lactamase hydrolysis compared with the other agents, and its utility is correspondingly diminished. It has been primarily used to treat sinusitis, otitis, or lower respiratory tract infections, in which these organisms have an important role.
Third-generation agents are less active against gram-positive cocci as are the first- and second-generation. However, in addition to the gram-negative bacteria inhibited by other cephalosporins, third-generation drugs are active against Serratia, Enterobacter as well as β-lactamase-producing strains of Haemophilus and Neisseria. Ceftazidime and cefoperazone are useful against Pseudomonas aeruginosa. Some cephalosporins (ceftriaxone, cefotaxime) are able to cross the blood-brain barrier.
Third-generation cephalosporins are used in the treatment of serious gram-negative bacterial infections, including septicemia, bone infections, female pelvic and intra-abdominal infections, and urinary tract infections caused by organisms that are resistant to most other drugs. Ceftriaxone and cefotaxime are first-line drugs for treatment of gonorrhea, meningitis. They are the most active cephalosporins against penicillin-resistant strains of pneumococci and are recommended for empirical therapy of serious infections that may be caused by these strains.
The excretion of cefoperazone and ceftriaxone is mainly through the biliary tract, and no dosage adjustment is required in renal insufficiency. The others are excreted by the kidney and therefore require dosage adjustment in renal insufficiency.
Cefepime is an example of a so-called fourth-generation cephalosporin. It is in many ways similar to third-generation agents, but it is more resistant to hydrolysis by chromosomal beta-lactamases (e.g., those produced by Enterobacter), that inactivate many of the third-generation cephalosporins. It has good activity against Pseudomonas aeruginosa. The clinical role of cefepime, which remains to be defined, will probably be similar to that of the third-generation cephalosporins except that it may be useful in treatment of infections caused by Enterobacter.
Adverse effects. Cephalosporins are sensitizing and may elicit skin rashes, pruritus, fever, granulocytopenia, and hemolytic anemia. The frequency of cross-allergenicity between cephalosporins and penicillins is around 5-10%. Local irritation can produce severe pain after i.m. injection and thrombophlebitis after i.v. injection. Renal toxicity, including interstitial nephritis has been caused by cephaloridine. Moxalactam, cefoperazone could cause hypoprothrombinemia, bleeding disorders, and disulfiram-like reactions. Many second- and particularly third-generation cephalosporins are ineffective against gram-positive organisms, especially methicillin-resistant staphylococci and enterococci. During treatment superinfection, mycosis may appear.
The representative of this group is aztreonam. This is drug with a monocyclic β-lactam ring. Aztreonam inhibit bacterial cell wall synthesis and act’s bactericidal. It is relatively resistant to β-lactamases and active against gram-negative rods (including Pseudomonas, Klebsiella, Serratia, and Proteus mirabilis). However, it has no activity against gram-positive bacteria or anaerobes. It resembles aminoglycosides in its spectrum of activity. Aztreonam is given i.v. or i.m. every 8 hours in a dose of 1-2 g. It is rapidly and widely distributed to body fluids and tissues. The half-life is 1-2 hours. It is excreted via kidneys (60-75% excreted unchanged). Aztreonam is indicated in the treatment of bacterial pneumonia, skin and soft tissue infections, urinary tract infections, gynecologic and intra-abdominal infections, septicemia. Penicillin-allergic patients tolerate aztreonam without reaction. Occasional skin rashes and phlebitis at the injection site may occur.
The carbapenems are structurally related to β-lactam antibiotics. Imipenem and meropenem are the two that are available. They have a wide spectrum with good activity against many gram-negative rods (Pseudomonas, Enterobacter, Serratia), gram-positive organisms, and anaerobes. They are resistant to most β-lactamases.
Carbapenems penetrates body tissues and fluids well, including the cerebrospinal fluid; the half-life is about 1-1,5 hours. Imipenem is inactivated by dehydropeptidase in renal tubules, resulting in low urinary concentrations. Consequently, it is administered together with an inhibitor of renal dehydropeptidase, cilastatin, for clinical use. Tienam is example of such combination. Meropenem is not significantly degraded by renal dehydropeptidase and does not require an inhibitor. It is primarily excreted unchanged by kidneys. The usual dose is given i.v. or i.m. every 6-8 hours. Carbapenems are indicated in the treatment of intra-abdominal infections, skin and soft tissue infections caused by susceptible organisms. They have the same mechanism action as aztreonam.
The most common adverse effects of carbopenems are nausea, vomiting, diarrhea, skin rashes, and reactions at the infusion sites. Carbapenems may lead to seizures in patients with a prior history of seizures or CNS abnormality. Patients allergic to penicillins or cephalosporins may be allergic to carbapenems as well.
The macrolides characterized by a macrocyclic lactone ring (usually containing 14 or 16 atoms) to which deoxy sugars are attached. Erythromycin is obtained from Streptomyces erythreus (since 1952), oleandomycin – from Streptomyces antibioticus. Clarithromycin and azithromycin are semisynthetic derivatives of erythromycin. Macrolides are effective against gram-positive organisms (pneumo-, strepto-, staphylococci, and corynebacteria), Mycoplasma, Legionella, Chlamydia trachomatis, Treponema pallidum, and Rickettsia species. The antibacterial action of macrolides is bacteriostatic. They inhibit protein synthesis via binding to the ribosomal RNA and blocking aminoacyl translocation reactions. Activity is enhanced at alkaline pH.
Erythromycin base is destroyed by stomach acid and must be administered with enteric coating. Food interferes with absorption. Bioavailability varies between 30 and 65%, depending on the salt. The serum half-life is approximately 1.5 hours. Large amounts of an administered dose are excreted in the bile and lost in feces. More than 90% of erythromycin is hepatically metabolized. Absorbed drug is distributed widely except to the brain and cerebrospinal fluid. Erythromycin is taken up by polymorphonuclear leukocytes and macrophages. It traverses the placenta and reaches the fetus. Duration of action is about 4-6 hours.
Erythromycin is the drug of choice in bronchitis, sinusitis, acute otitis media, and diphtheria, in chlamydial or mycoplasmal infections. It is also useful as a penicillin substitute in penicillin-allergic individuals with infections caused by staphylococci (assuming that the isolate is susceptible), streptococci, pneumococci, or Treponema pallidum.
Adverse reactions. Nausea, vomiting, diarrhea, and hypersensitivity reactions occasionally accompany erythromycin administration. Erythromycins, particularly the estolate, can produce acute cholestatic hepatitis. Erythromycin metabolites can inhibit cytochrome P-450 enzymes and thus increase the serum concentrations of theophylline, oral anticoagulants, and cyclosporine. In general, erythromycin has a low toxicity and can be taken by pregnant women (except erythromycin estolate). Erythromycin-resistant strains emerge frequently; they may appear after the first course therapy. That’s why the current utility of erythromycin is limited.
Oleandomycin is similar in antimicrobial activity and pharmacokinetic properties to erythromycin.
Clarithromycin is derived from erythromycin. This conversion improves acid stability and, therefore, oral absorption compared with erythromycin. Its mechanism of action is the same as that of erythromycin. Clarithromycin and erythromycin are virtually identical with respect to antibacterial activity except that clarithromycin is more active against Mycobacteria avium and leprae, Toxoplasma gondii. Erythromycin-resistant streptococci and staphylococci are also resistant to clarithromycin. Clarithromycin is well absorbed from the gastrointestinal tract; stable in gastric acid; food does not delay the extent of absorption; bioavailability is approximately 55%. It is widely distributed into tissues and fluids. Clarithromycin is metabolized in the liver. The major metabolite is 14-hydroxyclarithromycin, which also has antibacterial activity. The serum half-life depends on giving dose (about 4-7 hours). Excreted by kidneys. The advantages of clarithromycin compared with erythromycin are lower frequency of gastrointestinal intolerance and less frequent dosing. It can be taken twice daily.
Azithromycin 15-atom lactone macrolide rings compound is derived from erythromycin. Its spectrum of activity and clinical uses are virtually identical to those of clarithromycin. Azithromycin is slightly less active than erythromycin and clarithromycin against staphylococci and streptococci and slightly more active against Haemophilis influenzae and Chlamydia. Azithromycin differs from erythromycin and clarithromycin mainly in pharmacokinetic properties. It is rapidly absorbed and well tolerated orally. Food decreases bioavailability of azithromycin, which should be administered 1 hour before or 2 hours after meals. However, azithromycin penetrates into most tissues (except cerebrospinal fluid) and phagocytic cells extremely well, with tissue concentrations exceeding serum concentrations by 10- to 100-fold. Drug is slowly released from tissues (tissue half-life of 2-4 days) to produce an elimination half-life approaching 3 days. These unique properties permit once-daily dosing and shortening of the duration of treatment in many cases. For example, a single 1 g dose of azithromycin is as effective as a 7-day course of doxycycline for chlamydial cervicitis and urethritis. Azithromycin is indicated for treatment tonsillitis, bronchitis, pneumonia, acute otitis media, cervicitis or urethritis, pelvic inflammatory, skin and soft. It may cause nausea, vomiting, and diarrhea.
Aminoglycosides are a group that includes streptomycin, neomycin, kanamycin, amikacin, gentamicin, tobramycin, sisomicin, and others. Aminoglycosides have a hexose ring, either streptidine (in streptomycin) or 2-deoxystreptamine (other aminoglycosides), to which various amino sugars are attached by glycosidic linkages. They are water-soluble, stable in solution, and more active at alkaline than at acid pH.
Aminoglycosides binds to specific subunit ribosomal proteins and irreversible inhibits the protein synthesis; they act bactericidal. The transport of aminoglycosides across the cell membrane into the cytoplasm may be enhanced by cell wall-active drugs, such as penicillin or vancomycin; this enhancement may be the basis of the synergism. The spectrum of aminoglycosides covers aerobic gram-negative bacilli, and some gram-positive organisms. They are generally active against Pseudomonas, Escherichia coli, Proteus, Enterobacter, Klebsiella, Serratia species, Enterococcus faecalis and staphylococci. They are not active against anaerobic organisms.
Aminoglycosides are absorbed very poorly from the gastrointestinal tract. After i.m. injection, aminoglycosides are well absorbed, giving peak concentrations in blood within 1-2 hours. Aminoglycosides have been administered in two or three equally divided daily doses.
Aminoglycosides are highly polar compounds that do not enter cells readily. They distributed primary to extracellular fluid (urine, serum, abscesses, and synovial fluids), however low concentrations found in bile, breast milk, and cerebral spinal fluid. Also distributed to all body tissues, where aminoglycosides accumulate intracellularly. High concentrations found in highly perfused organs (liver, lungs, and kidneys), but lower concentrations are seen in muscle, fat, and bone. They cross the placenta. All aminoglycosides has a low protein binding (0 to 10%). They are not metabolized. Aminoglycosides are cleared by the kidney. The normal half-life in serum is 2-3 hours.
Aminoglycosides are indicated in the treatment of serious systemic infections caused by gram-negative enteric bacteria for which less toxic antibacterials are ineffective or contraindicated. They are almost always used in combination with a β-lactam antibiotic in order to extend coverage to include potential gram-positive pathogens and to take advantage of the synergism between these two classes of drugs.
Adverse effects. All aminoglycosides are ototoxic and nephrotoxic. These effects are more likely to be encountered when therapy is continued for more than 5 days, at higher doses, in the elderly, and in the setting of renal insufficiency. Ototoxicity can manifest itself either as auditory damage (tinnitus and high-frequency hearing loss); or as vestibular damage (vertigo, ataxia, and loss of balance). Nephrotoxicity results in rising serum creatinine levels. Concurrent use with loop diuretics (furosemide) or other nephrotoxic antimicrobial agents (amphotericin B) can potentiate nephrotoxicity. In very high doses, aminoglycosides can produce a curare-like effect with neuromuscular blockade that results in respiratory paralysis. Hypersensitivity occurs infrequently.
Streptomycin is the oldest and beststudied of the aminoglycosides. It is obtained from a strain of Streptomyces globisporus streptomycini. The antimicrobial activity of streptomycin is typical of that of other aminoglycosides. Resistance has emerged in most species, severely limiting the current usefulness of streptomycin, with the exceptions listed below. Streptomycin is used primarily as an antitubercular and is active against Mycobacterium tuberculosis and M. bovis. It is also considered the drug of choice for the treatment of infections caused by Francisella tularensis and Yersinia pestis, and is often used to treat Brucella infections in combination with tetracycline. Penicillin plus streptomycin is effective for enterococcal endocarditis. Fever, skin rashes, and other allergic manifestations may result from hypersensitivity to streptomycin. Pain at the injection site is common. The most serious toxic effect is disturbance of vestibular function. Vestibular toxicity tends to be irreversible. Streptomycin given during pregnancy can cause deafness in the newborn.
Neomycin is a combination of antibiotics neomycins A, B, C, that synthesized by Actinomyces fradiae. It is active against gram-positive and gram-negative bacteria and some mycobacteria. Streptococci are generally resistant. A mechanism of antibacterial action is the same as with other aminoglycosides. Neomycin is not significantly absorbed from the gastrointestinal tract. After oral administration, the intestinal flora is suppressed or modified and the drug is excreted in the feces. Excretion of absorbed drug is mainly through glomerular filtration into the urine.
Neomycin is used widespreadly in bowel preparation for colon surgery. This reduces the aerobic bowel flora with little effect on anaerobes. Also it can be prescribed for topical administration as solution or ointment on infected surfaces or abscess cavities where infection is present. Topically neomycin can be added by glucocorticoids. Such combination will cause antimicrobes and anti-inflammatory effects. Resistance to neomycin appear more rare comparatively with other aminoglycosides. Neomycin is too toxic for parenteral use. It has significant nephrotoxicity and ototoxicity. Auditory function is affected more than vestibular. Deafness has occurred.
Gentamicin is an aminoglycoside isolated from Micromonospora purpurea. It is effective against both gram-positive and gram-negative organisms, and many of its properties resemble those of other aminoglycosides. Gentamicin as much as tobramycin, and amikacin are the most widely employed aminoglycosides at present. Gentamicin is used mainly in severe infections e.g., sepsis, intra-abdominal and urinary tract infections, meningitis, skin and soft tissues infections, bacterial pneumonia caused by gram-negative bacteria that are likely to be resistant to other drugs. It is also used concurrently with penicillins for bactericidal activity in endocarditis. Gentamicin should not be used as a single agent to treat staphylococcal infections because resistance develops rapidly.
Gentamicin can be used i.v., i.m. or topically. The daily dose of gentamicin is divided into three equal amounts and given every 8 hours. Creams, ointments, or solutions have been used for the treatment of infected burns, wounds, or skin lesions and the prevention of intravenous catheter infections. It can exhibit reversible and usually mild nephrotoxicity. Ototoxicity, which tends to be irreversible, manifests itself mainly as vestibular dysfunction, perhaps due to destruction of hair cells by prolonged elevated drug levels. Loss of hearing can also occur.
Tobramycin has an antibacterial spectrum similar to that of gentamicin. While there is some cross-resistance between gentamicin and tobramycin, although a few organisms resistant to gentamicin remain susceptible to tobramycin. Tobramycin has almost the same antibacterial spectrum as gentamicin with a few exceptions. Tobramycin is slightly more active against Pseudomonas than others aminoglycosides. Gentamicin and tobramycin are otherwise completely interchangeable clinically. The pharmacokinetic properties of tobramycin are virtually identical to those of gentamicin. Like other aminoglycosides, tobramycin is ototoxic and nephrotoxic. Nephrotoxicity of tobramycin may be slightly less than that of gentamicin.
Sisomicin is similar in spectrum and indication to gentamicin. But it has higher antimicrobial activity and less toxic, than gentamicin.
Amikacin is a semisynthetic derivative of kanamycin; it is less toxic than the parent molecule. Amikacin is similar to gentamicin and tobramycin in its spectrum of activity; however, amikacin has the advantage of not being inactivated by the same enzymes. Thus, it therefore can be employed against some microorganisms resistant to the latter drugs. Many gram-negative enteric bacteria, including many strains of Proteus, Pseudomonas, Enterobacter, Serratia, and Mycobacterium tuberculosis, including streptomycin-resistant strains are inhibited by amikacin. Like all aminoglycosides, amikacin is nephrotoxic and ototoxic (particularly for the auditory portion of the eighth nerve).
Levomycetin (Chloramphenicol) can be isolated from cultures of Streptomyces venezuelae and can be synthesized chemically. It is soluble in alcohol but poorly soluble in water. Levomycetin succinate, which is used for parenteral administration, is highly water-soluble. It is hydrolyzed in vivo with liberation of free levomycetin. Levomycetin is a bacteriostatic broad-spectrum antibiotic that is active against aerobic both gram-positive and gram-negative organisms, including Shigella species, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis. Bacteria that are generally considered to be resistant to levomycetin include Pseudomonas aeruginosa, Enterobacter species, and Enterococcus faecalis. Forming of resistance to levomycetin is quite slow. Levomycetin is a potent inhibitor of microbial protein synthesis. It binds reversibly to the 50S subunit of the bacterial ribosome. It inhibits the peptidyl transferase step of protein synthesis.
Levomycetin is rapidly and completely absorbed from gastrointestinal tract (bioavailability - 80%). After absorption, it is widely distributed to virtually all tissues and body fluids, including the breast milk, central nervous system and cerebrospinal fluid such that the concentration of levomycetin in brain tissue may be equal to that in serum. It crosses placenta. The drug penetrates cell membranes readily. The protein binding is moderate (50%). Most of levomycetin (90%) is inactivated by conjugation with glucuronic acid in the liver. The therapeutic concentration of drug in serum is remained during 4-6 hours. Excretion of active levomycetin (about 10% of the total dose administered) and of inactive degradation products occurs by way of the urine. The daily dose is divided in three-four times.
Because of this drug's serious toxicity, levomycetin is indicated only for the treatment of serious infections in which less toxic antibacterials are ineffective or contraindicated. Levomycetin is indicated for the treatment of tularemia, plague, brucellosis, meningitis, caused by Haemophilis influenzae, Neisseria meningitidis; typhoid fever, caused by Salmonella typhi. It is also used in the treatment of rickettsial infections. Levomycetin-resistance strains are appearing slowly.
Adverse reactions. Occasionally develop nausea, vomiting, and diarrhea. Oral or vaginal candidiasis may occur as a result of alteration of normal microbial flora. Levomycetin commonly causes a dose-related reversible bone marrow depression: reticulocytopenia, anemia, and granulocytopenia. Aplastic anemia is an idiosyncratic reaction unrelated to dose. It tends to be irreversible and can be fatal. Hypersensitivity (rash, pruritus, fever), neurotoxic reactions (confusion, headache, and blurred vision) may elicit.
Newborn infants lack an effective glucuronic acid conjugation mechanism for the degradation and detoxication of levomycetin. Consequently, when infants are given levomycetin, the drug may accumulate, resulting in the gray baby syndrome, with vomiting, flaccidity, hypothermia, gray color, shock, and collapse. To avoid this toxic effect, levomycetin should be used with caution in full-term and premature infants.
Levomycetin inhibits hepatic microsomal enzymes that metabolize several drugs. Half-life is prolonged, and the serum concentrations of phenytoin, tolbutamide, and chlorpropamide are increased. Like other bacteriostatic inhibitors of microbial protein synthesis, levomycetin can antagonize bactericidal drugs such as penicillins or aminoglycosides.
The tetracyclines are a large group of drugs with a common basic structure and activity. Tetracycline is isolated from Streptomyces; oxytetracycline is derived from Streptomyces rimosus. Methacycline and doxycycline, semisynthetic antibiotics, are the derivatives of tetracycline and oxytetracycline, respectively. Free tetracyclines are substances of low solubility. They are available as hydrochlorides, which are more soluble. Tetracyclines are broad-spectrum antibiotics that inhibit protein synthesis. Tetracyclines 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.
The antibacterial activities of most tetracyclines are similar. Differences in clinical efficacy are minor and attributable largely to features of absorption, distribution, and excretion of individual drugs. They are bacteriostatic for many gram-positive and gram-negative bacteria, including anaerobes, Escherichia coli, Shigella, rickettsiae, chlamydiae, mycoplasmas, meningo- gono-, streptococci, and are active against some protozoa, e.g., amebas.
Absorption after oral administration is approximately 60-70% for tetracycline, oxytetracycline, and methacycline; and 95-100% for doxycycline. A portion of an orally administered dose of tetracycline remains in the gut lumen, modifies intestinal flora, and is excreted in the feces. Absorption is impaired by food (except doxycycline), by cations Ca2+, Mg 2+, Fe2+, or Al3+, and by alkaline pH. Tetracyclines are 40-80% bound by serum proteins. Tetracyclines are distributed widely to tissues and body fluids except for cerebrospinal fluid. Tetracyclines tend to localize in bone, liver, spleen, tumors, and teeth. They cross the placenta and are also excreted in milk. Tetracyclines are excreted unchanged mainly in bile and urine, mainly by glomerular filtration. Some of the drug excreted in bile is reabsorbed from the intestine (enterohepatic circulation) and contributes to maintenance of serum levels. 20-40% of tetracyclines in the body is excreted in feces. Doxycycline, in contrast to other tetracyclines, primary is eliminated with feces (90%), does not accumulate significantly in renal failure.
Tetracyclines are classified as short acting (tetracycline, oxytetracycline), intermediate acting (methacycline), or long acting (doxycycline) based on serum half-lives of 6-8 hours, 12 hours, and 16-20 hours, respectively.
Systemic tetracyclines are indicated in the treatment of bronchitis, pharyngitis, pneumonia, sinusitis, septicemia, and intra-abdominal and genitourinary tract infections. They can be used in the treatment of chlamydial infections, gonorrhea, bacillary and amebic dysentery, syphilis, trachoma, rickettsial infections, cholera. A tetracycline - usually in combination with an aminoglycoside is indicated for plague, tularemia, and brucellosis.
Adverse reactions. Nausea, vomiting, stomatitis, glossitis, and diarrhea are the most common reasons for discontinuing tetracycline medication. These effects are attributable to direct local irritation of the intestinal tract. That’s why, i.v. injection can lead to venous thrombosis, i.m. injection produces painful local irritation. Tetracyclines modify the normal flora, with suppression of susceptible coliform organisms and overgrowth of Pseudomonas, Proteus, staphylococci, clostridia, and Candida. This can result in intestinal functional disturbances, anal pruritus, vaginal or oral candidiasis, or pseudomembranous enterocolitis. Tetracyclines are readily bound to calcium deposited in newly formed bone or teeth in infants and children under 8 years of age. It can be deposited in the fetal teeth, leading to fluorescence, discoloration, and enamel dysplasia; it can also be deposited in bone, where it may cause deformity or growth inhibition. It is also contraindicated during pregnancy. Sometimes hypersensitivity reactions (fever, skin rashes, and photosensitization) may occur.
The polymyxins are a group of basic peptides active against gram-negative bacteria. They are formed by Bacillus polymyxa. To this group belongs polymyxin M sulfate and polymyxin B sulfate. The sulfates are water-soluble and very stable. Polymyxins are bactericidal for many gram-negative rods, including E. coli, Shigella, and Pseudomonas. Gram-positive organisms, Proteus, and Neisseria are resistant. In susceptible bacterial populations, resistant mutants are rare. Polymyxins act like cationic detergents. They attach to bacterial cell membranes, increase it permeability, and microbes cell essential substance are going outside. Polymyxins are active against extracellular microbes only. They also bind and inactivate endotoxin.
Polymyxin M is not used for systemic administration because of it poor tissue distribution; it substantial nephrotoxicity and neurotoxicity. Polymyxin M can be used locally. Commonly it is applied concurrently with neomycin to infected superficial skin lesions (burns, ulcers, abscesses) caused by susceptible microorganisms. Local reactions and hypersensitivity to topical administration are rare.
Polymyxin B is used i.m., i.v. and orally. Polymyxin B sulfates is not absorbed from the normal alimentary tract, thus it is used for the treatment of enterocolitis, in bowel preparation for colon surgery. Active blood level is low. Repeated injections may give a cumulative effect. The drug is excreted slowly by the kidneys. Tissue diffusion is poor and the drug does not pass the blood brain barrier into the cerebrospinal fluid. That’s why, in meningeal infections, polymyxin B sulfate should be administered only by the intrathecal route. It may be indicated for serious infections caused by susceptible strains, when less potentially toxic drugs are ineffective or contraindicated. Polymyxin B is a drug of choice in the treatment of infections of the urinary tract, skin, meninges, and bloodstream caused by Pseudomonas aeruginosa. It may be indicated for the treatment of pneumonia, bacteremia caused by Klebsiella pneumoniae.
Parenterally it should be given only to hospitalized patients, so as to provide constant supervision by a physician. Patients with nephrotoxicity due to polymyxin B sulfate usually show albuminuria, cellular casts, and azotemia. Neurotoxic reactions may be manifested by drowsiness, ataxia, perioral paresthesia, numbness of the extremities, and blurring of vision. The concurrent use of other nephrotoxic and neurotoxic drugs, particularly aminoglycosides, cephaloridine should be avoided. The neurotoxicity of polymyxin B sulfate can result in respiratory paralysis from neuromuscular blockade, especially when the drug is given soon after anesthesia and/or muscle relaxants. As with other antibiotics, use of this drug may result in superinfection, allergic reactions. It can cause severe pain at i.m. injection sites, and thrombophlebitis at i.v. injection sites.
Lincomycin is elaborated by Streptomyces lincolnensis. It resembles erythromycin in activity. Streptococci, staphylococci, pneumococci, and anaerobes (Bacteroides species, Clostridium tetani, Cl. perfringens) are inhibited by lincomycin. Enterococci and gram-negative aerobic organisms are resistant. Clostridium difficile, an important cause of pseudomembranous colitis, is resistant. Lincomycin, like erythromycin, inhibits protein synthesis. It is usually considered bacteriostatic. Resistance to lincomycin is generally confers cross-resistance to other macrolides.
Lincomycin rapidly absorbed from the gastrointestinal tract following oral administration; absorption decreased when taken with food. It can be injected i.m. or i.v. Widely and rapidly distributed to most fluids and tissues, except cerebrospinal fluid; high concentrations in bone, bile, and urine. Lincomycin readily crosses the placenta; also distributed into breast milk. Biotransformation takes place in liver. Half-life is about 4-6 hours. Lincomycin is eliminated by urine and bile.
The most important indication for lincomycin is the treatment of severe infections caused by susceptible strains of streptococci, pneumococci, and staphylococci, as much as anaerobic infection. Lincomycin form a high antimicrobial concentration in bones, thus it can be used for the osteomyelitis treatment.
Common adverse effects are diarrhea, nausea, and skin rashes. Impaired liver function (with or without jaundice) and neutropenia sometimes occur. Pseudomembranous colitis (severe diarrhea, fever), that followed lincomycin administration, is caused by Clostridium difficile. This potentially fatal complication must be treated with metronidazole or vancomycin.
Clindamycin is a chlorine-substituted derivative of lincomycin. It is similar in spectrum activity and using to lincomycin, however, it has higher antimicrobial activity.
Vancomycin is a glycopeptide antibiotic produced by Streptococcus orientalis. It is active mainly against gram-positive bacteria, particularly staphylococci and anaerobes, including Clostridium difficale. It is resistance to β-lactamase. Vancomycin inhibits cell wall synthesis. It also may alter the permeability of bacterial cytoplasmic membranes and may selectively inhibit ribonucleic acid synthesis. It is poorly absorbed from the intestinal tract and is administered orally only for the treatment of antibiotic-associated enterocolitis caused by Clostridium difficile. Parenteral doses must be administered intravenously. The drug is widely distributed in the body. 80-90% of the drug is excreted unchanged by glomerular filtration.
The main indication for parenteral vancomycin is sepsis or endocarditis caused by penicillin-resistant staphylococci. Vancomycin is irritating to tissue, resulting in phlebitis at the site of injection. Ototoxicity and nephrotoxicity are uncommon and mild with current preparations. However, administration with another ototoxic or nephrotoxic drug, such as an aminoglycoside, increases the risk of these toxicity.
Fusidic acid is antibiotic broad-spectrum activity. Usually it is used as fusidine sodium. It is active against staphylococci, meningococci, and gonococci. Fusidine inhibit the protein synthesis; acts bacteriostatic. Well absorbed in gastro-intestinal tract. It is distributed widely to tissues and body fluids. Agent tends to localize in bones. Fusidine is metabolized in liver and excreted by bile. Primary fusidine is indicated for the treatment of disease caused by penicillin-resistant staphylococci. Adverse effects: nausea, vomiting, rash, jaundice.
Sulfanilamides (sulfonamides) are synthetic derivatives of p-aminobenzenesulfon-amide (sulfanilamide). If the N4-amino group is replaced with radicals that can be converted to a free amino group in the body, the compound retains antibacterial activity. Substitution in the N1-amide group produces compounds varying in solubility, protein binding, tissue distribution, and rate and mode of metabolism and excretion. Sulfanilamides generally are insoluble in water. The drugs are weak acids and form salts with bases; their sodium salts are very soluble in water. Solutions of the sodium salts of most sulfonamides are strongly basic.
Prontosil (red streptocidum) was one of the dyes included by G. Domagk to treat experimental streptococcal infection in mice at 1935 and found it to be highly effective. Since that time the usage of sulfanilamides has begun. All sulfanilamide medicines are the products of streptocidic amide group hydrogen atom replacement by various radicals. The differences between them are efficiency rate and terms only.
Mechanism of action. Sulfanilamides are structural analogs of PABA (para-aminobenzoic acid) and appear to interfere with PABA utilization by competitively inhibiting the enzyme dihydropteroate synthase, which catalyzes the formation of dihydropteroic acid (a precursor of tetrahydrofolic acid), from PABA and pteridine. Sulfanilamides are usually bacteriostatic in action. Only microorganisms that synthesize their own folic acid are inhibited by sulfanilamides; animal cells and bacteria which are capable of utilizing folic acid precursors or preformed folic acid (tetrahydrofolic acid) are not affected by these drugs. Novocaine is a PABA derivative: it antagonizes sulfanilamides. The antibacterial activity of the sulfanilamides is reportedly decreased in the presence of pus, blood or purulent body exudate, because they contain purines and thymidine that decrease bacterial requirement for folic acid.
Spectrum of activity. Sulfanilamides are active against gram-positive bacteria including some strains of staphylococci, streptococci, Bacillus anthracis, Clostridium tetani, and C. perfringens. The drugs are active in vitro against Enterobacter, Escherichia coli, Klebsiella, Proteus mirabilis, P. vulgaris, Salmonella, and Shigella. Sulfanilamides are active against some strains of Neisseria gonorrhea, Chlamydia trachomatis and also have some activity against Toxoplasma gondii and Plasmodium.
Organisms initially sensitive to sulfanilamides may develop resistance. Sulfanilamide-resistant strains emerge frequently when therapy is continued for 15 days or longer. Because of the availability of many safer and more effective antibiotics, sulfanilamides current utility is limited.
A. Sulfanilamides which are well absorbed from gastro-intestinal system, with resorbtive action:
a) short acting (T1/2 about 8 h) - streptocidum, norsulfazolum (sulfathiazolum sodium), sulfadimezinum (sulfadimidine), urosulfanum (sulfacarbamid), aethazolum (sulfaethidole);
b) intermediate acting (T1/2 lesser 12-14 h) - sulfazinum (sulfadiazinum), me-tylsulfazinum, sulfamethoxazolum;
c) long action time (T1/2 about 24-28 h) – sulfapyridazinum (sulfamethoxypyridazine), sulfamonomethoxinum, sulfadimethoxinum;
d) ultralong action time (T1/2 about 65 h) –sulfalenum (sulfametopyrazine).
B. Sulfanilamides which are badly absorbed from gastro-intestinal system, used for healing of intestinal infections - sulginum (sulfguanidine), phthalazolum (phthalylsulfathiazolum), phthazinum.
C. Combined preparations:
a) combination with salicylic acid for healing of non-specific ulceral colitis – salazopyridazinum (salazodin), salazolsulfapyridinum (sulfasalazin);
b) preparations containing trimethoprim – co-trimaxazole (biseptol), sulfatonum.
D. Preparations for local use - sulfacylum-sodium (sodium sulfacetamide), maphenidum, sulfazini silver (silver sulfadiazine). Sodium salts of sulfanilamides.
Approximately 70-90% of an oral dose of the absorbable sulfanilamides is reportedly absorbed from the small intestine. Norsulfazole, sulfadimezine, aethazole, and urosulfane are absorbed rapidly; peak blood concentrations are usually obtained within 2-4 hours. Sulfazine, sulfamethoxazole and sulfapyridazine are absorbed at a slower rate with peak blood concentrations occurring within 3-7 hours. Absorbable sulfanilamides are widely distributed in the body. They may appear in breast milk, synovials and cerebrospinal fluids. Sulfanilamides readily cross the placenta.
Sulfanilamides are bound in varying degrees to plasma proteins. Sulfazinum, norsulfazolum are reportedly 12-50% bound to plasma proteins and sulfadimethoxinum and sulfapyridazinum are reportedly 85-90% bound to plasma proteins.
A portion of absorbed drug is mostly acetylated and also glucuronidated in the liver. The rate of sulfanilamides acetylation is differ each other – urosulfanum, aethazolum has the lowest extend, and streptocidum, sulfadimezinum – the highest. The metabolites do not possess antibacterial activity. N4-acetyl metabolites are usually less soluble than the parent sulfanilamide, particularly in acidic urine, however, glucuronide derivatives are water soluble. Sulfanilamides and their metabolites are excreted mainly by the kidneys via glomerular filtration. Alkalization of urine increases the solubility of sulfanilamides and decreases tubular reabsorption, resulting in increases renal excretion of the drugs. Except for the poorly absorbed sulfanilamides only small amounts of sulfanilamides are excreted in feces.
The basic principles of sulfanilamide chemotherapy are following. The first dose (blowing dose) of absorbable sulfanilamides must be in two times bigger than subsequent doses (keeping up dose), except co-trimaxazole. The sulfanilamide therapy has to be continued during 2-3 days after clinical recover (“sulfanilamide train”). Patients also have to drink a lot (1,5-2 liters a day) of alkaline water.
1. Urosulfanum, aethazolum are highly soluble (free as well as acetylated form) even in acidic urine – crystalluria is less likely. More than 60% is excreted unchanged in urine. They are highly desirable for urinary tract infections, including pyelonephritis, pyelitis. They must be taken four times a day.
2. Norsulfazolum, sulfadimezinum are also rapidly absorbed, very little acetylated and quickly excreted in urine. They can be used for the tretament of meningitis, pneumonia and other infection diseases. In addition sulfadimezinum is indicated for toxoplasmosis and gonorrhea.
3. Sulfazinum has slower oral absorption and urinary excretion. It used on twice daily schedule for pneumonia, bronchitis, and malaria treatment.
4. Sulfapyridazinum, sulfadimethoxinum are highly protein bound, lipid soluble, and slowly excreted sulfanilamides. They used once a day for the treatment of pneumonia, otitis, bile duct and urinary tract infections, malaria, lepra, sulfapyridazinum - also for meningitis.
5. Sulfalenum is ultralong acting compound, action lasting more than 7 days. It has been used in the treatment of malaria, infections of bile duct and urinary tract. Sulfalenum can be taken orally 0,2g (1 tab) every day or 2g once a week.
6. Sulginum, phthalazolum have N4 as well as N1 substitution. That’s why, they are not active as such and are not absorbed in the small intestine. In the bowel, bacteria split off the N4 substitution to release sulfanilamide, which is active locally. These agents have been used for colitis, gastroenteritis, and dysentery and for preparation of bowel before colonic surgery. Small amount of sulfanilamide that gets absorbed can cause toxicity including crystalluria.
7. Salazopyridazinum, salazolsulfapyridinum are splited by intestinal microflora to yield sulfapyridazinum and 5-aminosalicylate in first case; sulfapyridinum and 5-aminosalicylate in second case. They are widely used in ulcerative colitis, enteritis, and other inflammatory bowel diseases. Salicylate is released in the colon in high concentration and is responsible for an anti-inflammatory effect, the major source of benefit from this drug. Comparably high concentrations of salicylate cannot be achieved in the colon by oral intake of ordinary formulations of salicylates because of severe gastrointestinal toxicity. In addition, it was found to suppress the disease in significant number of rheumatoid arthritis patients.
8. Co-trimaxazole is the combination of sulfamethoxazolum with trimethoprim. Trimethoprim is a diaminopyrimidine derivative, it selectively inhibits bacterial dihydrofolate reductase. The two drugs cause sequential block of folate metabolism (see table 3.1.). Individually both sulfanilamides and trimethoprim are primarily bacteriostatic, but the combination becomes cidal against many organisms. Trimethoprim is about 50000 times more active against bacterial dihydrofolata reductasa than against mammalian enzyme. Thus, human folate metabolism is not interfered at antibacterial concentration of trimethoprim.
Trimethoprim is usually given orally, alone or in combination with sulfamethoxazole, the latter chosen because it has a similar half-life. Trimethoprim is absorbed well from the gut and distributed widely in body fluids and tissues, including cerebrospinal fluid. Because trimethoprim is more lipid-soluble than sulfamethoxazole, it has a larger volume of distribution than the latter drug. Therefore, when 1 part of trimethoprim is given with 5 parts of sulfamethoxazole (the ratio in the formulation), the peak plasma concentrations are in the ratio of 1:20, which is optimal for the combined effects of these drugs in vitro. About 65-70% of each participant drug is protein-bound, and 30-50% of the sulfanilamide and 50-60% of the trimethoprim (or their respective metabolites) are excreted in the urine within 24 hours.
Sensitive to trimethoprim-sulfamethoxazole combination are Escherichia coli, Salmonella typhi, Proteus mirabilis, and Klebsiella pneumoniae, Enterobacter, Pneumocystis carinii, many stains of Staphylococcus. A combination of trimethoprim-sulfamethoxazole is effective treatment for chronic bronchitis, pneumonia, urinary tract infections (cystitis, pyelonephritis, pyelitis), prostatitis, shigellosis, typhoid fever, and many others. It is the agent of choice Pneumocystis carinii pneumonia, especially in patients with AIDS. It may be used for gram-negative bacterial sepsis, including that caused by some multiple-drugresistant species such as Enterobacter and Serratia.
Trimethoprim produces the predictable adverse effects of an antifolate drug, especially megaloblastic anemia, and leukopenia. This can be prevented by the simultaneous administration of folinic acid, 6-8 mg/d. In addition, the combination trimethoptrm-sulfamethoxazole may cause all of the untoward reactions associated with sulfanilamides.
Sulfatonum is combination of sulfamonomethoxinum (0,25g) with trimethoprim (0,1g). It’s characteristic is similar to co-trimaxazole.
9. Sulfacylum-sodium ophthalmic solution or ointment is effective treatment for bacterial conjunctivitis and as adjunctive therapy for trachoma. It has been most commonly used for treatment and prevention of gonococcal ophthalmitis, including newborns.
10. Mafenidum is used topically to prevent bacterial colonization and infection of burn wounds. It does not inactivated by PABA.
11. Sulfazine silver is a much less toxic topical sulfanilamide and is preferred to mafenide for prevention of infection of burn wounds. It slowly releases silver and are used to suppress bacterial growth in burn wounds.
Adverse effects of the sulfanilamides are numerous. Although serious, in some cases fatal, reactions have been reported, they occur infrequently. Various dermatoid reactions, including rash, eosinophilia, pruritus, photosensitivity, Stevens-Johnson and serum sickness syndrome have been reported. Acute hemolytic anemia may occur as a result of sensitization or glucose-6-phosphate dehydrogenase (G-6-PD) deficiency. Adverse hematoid effects, including methemoglobinemia, sulfhemoglobinemia, leukopenia, aplastic anemia, thrombocytopenia, have been associated with sulfanilamide therapy. Renal damage, manifested by kidney stone formation, renal colic, toxic nephrosis is usually a result of crystalluria caused by precipitation of the sulfanilamide and/or its acetyl derivative in acid urine. Urinary alkalization may be achieved by administering 2.5-4 g of sodium bicarbonate orally every 4 hours. Nausea or vomiting, gastroenteritis, diarrhea also have been reported. Adverse neurology effects, including headache, dizziness, mental depression, fatigue, and acute psychosis may occur.
Drug interactions. Sulfanilamides may potentiate the effects of coumarin anticoagulants and oral antidiabetic agents by displacing them from their protein-binding sites. Some sulfanilamides may inhibit metabolism of phenytoin and should be used with caution in patients receiving the drug. Since hexamethylentetraminum (methenamine) requires acidic urine for its antibacterial effect, the drug should not be used concomitantly with less soluble sulfanilamides (e.g., sulfazine) which may crystallize in acidic urine.
DERIVATIVES OF DIFFERENT GROUPS
These are the medicines of a great efficiency spectrum. Their action mechanism is the turning of nitrogroup into the aminogroup and germs cellular respiration suppression. Medium concentrations are bacteriostatic, large doses become bactericide.
Microorganism’s resistance to nitrofurane derivatives develops slowly. No cross-resistance to antibiotics or sulfanilamides occurs. They may be combined with penicillins, streptomycin, other aminoglycosides and tetracyclines.
Furazolidone is a broad-spectrum anti-infective that is effective against most gastrointestinal tract pathogens. Furazolidone is active in vitro against Enterobacter aerogenes, Escherichia coli, Proteus species, Salmonella species, Shigella species, and staphylococci. It is indicated in the treatment of bacterial diarrhea caused by susceptible organisms. Furazolidone is indicated in the treatment of lambliosis (giardiasis) caused by Giardia lamblia, and for the treatment of trichomoniasis.
It is well absorbed following oral administration. It is rapidly and extensively metabolized. Furazolidone and furadoninum may cause the dark yellow to brown discoloration of urine. Furazolidone also acts as a monoamine oxidize (MAO) inhibitor. That’s why concurrent use of MAO inhibitors, tyramine- or other high pressor amine-containing foods and beverages, such as cheese; beer; liqueurs; smoked or pickled meat, or fish; and any overripe fruits with furazolidone may precipitate hypertension.
Patients should be advised not to drink alcoholic beverages while taking furazolidone and for 4 days after discontinuing it, because concurrent use of alcohol with furazolidone may rarely result in a disulfiram-like reaction, characterized by facial flushing, difficult breathing, slight fever, and tightness of the chest.
Hypersensitivity reactions (fever; itching; joint pain; skin rash or redness) hemolytic anemia in glucose-6-phosphate dehydrogenase deficiency patients, and gastrointestinal disturbances (abdominal pain, diarrhea, nausea, or vomiting) also may appear during furazolidone be used.
Furadoninum (nitrofurantoin) is indicated in the treatment of urinary tract infections caused by susceptible strains of Escherichia coli, enterococci, Staphylococcus aureus, Enterobacter species, and Proteus species.
Furadoninum is rapidly and completely absorbed in the small intestine. About 30%-40% of furadoninum is rapidly excreted unchanged. Therapeutic concentrations are achieved only in the urine, serum concentrations are very low.
Gastrointestinal disturbances and hypersensitivity reactions are the principal side effects of furadoninum. Hemolytic anemia can occur in glucose-6-phosphate dehydrogenase deficiency patients. Furadoninum also antagonizes the action of nalidixic acid. Both furazolidonum and furadoninum should preferably be taken with food or milk. This minimizes gastrointestinal irritation.
Quinolones are active against most of gram-negative organisms, including Proteus species, Klebsiella species, Enterobacter species, Salmonella species, Shigella species, and Escherichia coli. The majority of staphylococci strains are susceptible to quinolones. Quinolones appears to act by inhibiting bacterial DNA synthesis.
Nalidixic acid (negram) is the first antibacterial quinolone. It is the derivative of naftiridinum. It is bacteriostatic or bactericidal depending on the concentration. Resistance may develop rapidly during treatment.
Nalidixic acid rapidly and almost completely absorbed from the gastrointestinal tract. Since nalidixic acid achieves only low concentrations in the serum and is concentrated in the urine, it is indicated only in the treatment of urinary tract infections. Half-life of nalidixic acid in serum is about 1 to 2.5 hours; in urine – 6 hours. It crosses the placenta and is excreted in breast milk.
The main side effects are diarrhea, nausea, vomiting, hypersensitivity, dizziness, headache, seizures, photosensitivity (increased sensitivity of skin to sunlight). Since nalidixic acid and other related compounds have been shown to cause arthropathy in immature animals, use is not recommended in first three months of pregnancy and in children up to 2 years of age.
Oxolinic acid (gramurin) is similar in structure and function to nalidixic acid. It has higher antimicrobial activity, than nalidixic acid, but more neurotoxic.
Fluoroquinolones are synthetic fluorinated analogs of nalidixic acid. Fluorinated derivatives (ciprofloxacin, ofloxacin, and others) have greatly improved antibacterial activity compared with nalidixic acid and achieve bactericidal levels in blood and tissues. Their spectrum of antimicrobial activity is similar to first quinolones. In addition fluoroquinolones act on Pseudomonas, Neisseria, and Campylobacter, intracellular pathogens such as Legionella, Chlamydia, and some mycobacteria, including M. tuberculosis. Anaerobes generally are resistant. Fluoroquinolones block bacterial DNA synthesis by inhibiting bacterial topoisomerase II (DNA gyrase) that is required for normal transcription and replication. During fluoroquinolone therapy, resistant organisms emerge, especially among staphylococci, streptococci, Pseudomonas.
After oral administration, the fluoroquinolones are well-absorbed (bioavailability of 80-95%) and distributed widely in body fluids and tissues. They badly bind with serum proteins. Serum half-life range from 4 hours (ciprofloxacin) up to 8 hours (pefloxacin and ofloxacin). The fluoroquinolones are excreted mainly by kidney mostly unchanged.
Ciprofloxacin, pefloxacin, and ofloxacin are indicated in the treatment of urinary tract infections (cystitis, and pyelitis); bacterial prostatitis caused by susceptible organisms. Ciprofloxacin and ofloxacin are indicated in the treatment of bone and joint infections; skin and soft tissue infections; chronic bronchitis; pneumonia caused by susceptible organisms. Also they are indicated in the treatment of endocervical and urethral infections caused by N. gonorrhea. Finally parenteral ciprofloxacin is indicated in the treatment of septicemia caused by E. coli or S. typhi.
Adverse effects. Fluoroquinolones at an alkaline pH may form crystals that have resulted in crystalluria. Because normal urinary pH is acidic (approximately 5 to 6) crystalluria is very unlikely to occur. They also may leads to diarrhea, nausea or vomiting, hypersensitivity reactions, photosensitivity, CNS toxicity (dizziness; headache; drowsiness; insomnia; tremor). Very rarely seizure and acute psychosis may appear. Fluoroquinolones are not recommended for use during pregnancy, breast-feeding, in children, and adolescents because they have been shown to cause arthropathy in immature animals.
Fluoroquinolones inhibit the cytochrome oxidizing (P-450) enzyme system of liver that can intensify the effect of agents, which metabolized by these enzymes. For instance, concurrent use of theophylline (aminophylline, caffeine) with fluoroquinolones may result in a prolonged theophylline elimination half-life, increased serum concentration, and increased risk of theophylline-related toxicity.
8-Oxyquinolines (8-hydroxyquinoline) possess antimicrobial, antiprotozoal, and antifungal activity. Representatives of this group are chlorchinaldol, complex agent intestopanum, and nitroxoline (5-NOK).
Chlorchinaldol is used for the treatment of intestine infection diseases such as dysentery, salmonellosis, intestine infections caused by staphylococci, Proteus species, and another Enterobacter species. In addition it may be prescribed for amoebiasis and lambliosis. Chlorchinaldol is used orally. Most of an oral dose of the drug is not absorbed from the gastro-intestinal tract but is excreted in feces. It acts primarily in the intestinal lumen.
Adverse gastro-intestinal effects of chlorchinaldolum include nausea, vomiting, epigastric burning and pain, allergic reactions. The drug can cause optic neuritis, optic atrophy, and peripheral neuropathy, especially in children. Permanent loss of vision has occurred. Dysesthesia and weakness are reported to occur commonly in adults. Duration of chlorchinaldolum therapy less than 7 days.
Intestopanum is similar in activity and indications to chlorchinaldol.
Nitroxoline is distinguishing by rapid absorption from the gastrointestinal tract. It is excreted mainly by kidney mostly unchanged; thus it concentrated in urine. Nitroxoline can be used for urinary tract infections (pyelitis, cystitis). It causes the yellow discoloration of urine. In general it has low toxicity. Sometimes nausea and allergic reactions may occur.
Metronidazole acts microbicidally against most obligate anaerobic bacteria and protozoa (Trichomonas vaginalis, Giardia lamblia, and Entamoeba histolytica) by undergoing intracellular chemical reduction. Reduced metronidazole interacts with DNA to cause inhibition of nucleic acid synthesis and cell death. Metronidazole is indicated in the treatment of protozoal diseases (amoebiasis, lambliosis, trichomoniasis), bone, pelvic and intra-abdominal infections, endocarditis, septicemia caused by anaerobic bacteria (Bacteroides and Clostridium species). It is indicated for the prophylaxis of perioperative infections during colorectal surgery. Metronidazole can be prescribed for adjunct treatment of Helicobacter pylori-associated gastritis.
Metronidazole is well absorbed orally. It is widely distributed to tissues and fluids of organism; it crosses the placenta and blood-brain barrier, also. The half-life is about 8-10 hours. Metronidazole and its metabolites mostly eliminated by kidneys that cause the red to brown discoloration of urine.
Side effects of metronidazole are dry mouth, an unpleasant or sharp metallic taste, diarrhea, nausea or vomiting, loss of appetite, hypersensitivity, leukopenia, and vaginal candidiasis. It is contraindicated during active organic disease of the CNS, pregnancy, breast-feeding. Metronidazole not be used concurrently with, or for at least 1 day following, ingestion of alcohol, because disulfiram-like effects may occur.
Tinidazole is similar in structure and function to metronidazole. It is indicated in the treatment amoebiasis, lambliosis, and trichomoniasis. It acts longer than metronidazole.
Chinoxydinum and dioxydinum are active against Proteus vulgaris, cyanobacterium, Escherichia coli, Salmonella and Shigella species, staphylococci, Clostridium species. These agents are indicated for severe purulent inflammation, such as pyelocystitis, cholecystitis, abscess of lungs, empyema, septicemia, that caused by susceptible organisms. The agents can be used only in adults. Usually, chinoxydinum is taken orally and dioxydinum - locally, intracavitary and intravenous. During treatment nausea, vomiting, dizziness, headache, allergic rash, seizure of skeletal muscle can appear.
Tuberculosis, mycobacterial infection, is among the most difficult of all bacterial infections to cure. The lipid-rich mycobacterial cell wall is impermeable to many agents. A substantial proportion of mycobacterial organisms are intracellular, and inaccessible to drugs that penetrate poorly. Finally, mycobacteria are notorious for their ability to develop resistance to any single drug. Combinations of drugs are required to overcome these obstacles and to prevent emergence of resistance during the course of tuberculosis treatment. In practice, therapy is initiated with a 3-4-drug regimen. The response of Mycobacterium tuberculosis to chemotherapy is slow, and treatment must be administered for 6-12 months.
Classification of antituberculosis agents
A. Basic (first-line) agents:
a. antibiotics - streptomycin, rifampicin;
b. synthetic drugs – isoniazid, ethambutol.
B. Supplemental (second-line):
a. antibiotics – cycloserin, canamycin;
b. synthetic drugs – ethionamide, pyrazinamide, para-aminosalicylate sodium
Usually, basic agents are more effective and less toxic, than reserve agents are. Thus, basic agents are the drugs of first choice. The alternative drugs are usually considered only in the case of resistance to the drugs of first line and in case of the toxic effects. As the rule, synthetic drugs acts on mycobacteria only. However, antituberculosis antibiotics are the broad-spectrum antimicrobe’s agents.
Rifampicin (rifampin) is a semisynthetic derivative of rifamycin, an antibiotic produced by Streptomyces mediterranei. It is active in vitro against gram-positive and gram-negative cocci, some enteric bacteria (E. coli, Salmonella, some strains of Pseudomonas and Proteus), and mycobacteria. Administration of rifampicin as a single drug quickly selects the highly resistant organisms. Rifampicin binds strongly to the bacterial DNA-dependent RNA polymerase and thereby inhibits RNA synthesis. Human RNA polymerase does not bind rifampin and is not inhibited by it. Rifampicin is bactericidal for mycobacteria. It can kill microorganisms that are poorly accessible to many other drugs, such as intracellular organisms and those sequestered in abscesses and lung cavities.
Rifampicin is well absorbed after oral administration. Being lipid-soluble, rifampicin diffuses well to most body tissues and fluids, including the cerebrospinal fluid. Therapeutic concentrations are achieved in the saliva, sputum, bones, and pleural cavity. It crosses the placenta and is distributed into breast milk. Rifampicin is relatively highly protein-bound drug (90%). Agent rapidly deacetylated by auto-induced microsomal oxidative enzymes to metabolites. Rifampicin excreted mainly through the liver into bile and then undergoes enterohepatic recirculation. The rifampicin half-life initially 3-5 hours; with repeated administration, half-life decreases to 2-3 hours.
Rifampicin can be administered orally or i.v. The usual daily dose for adult is about 0,6 g given once a day. Rifamycin can be used i.v., i.m. or locally. Rifampicin is effective in tuberculosis and in leprosy. Rifampicin therapy is also indicated for treatment of bronchitis, pneumonia, osteomyelitis, and biliary tract infections caused by susceptible infections. Rifampicin imparts a harmless reddish-orange color to urine, sweat, and tears. Occasional adverse effects include itching, rash, diarrhea, stomach cramps, and leukopenia. It may cause cholestatic jaundice and occasionally hepatitis (see table 3.3). Rifampin induces microsomal enzymes (e.g., cytochrome P-450), which increases the elimination of numerous other drugs including oral anticoagulants, some anticonvulsants, and contraceptives. Rifampicin is not recommended during pregnancy, breast-feeding, and hepatitis.
The mechanism of action and the pharmacologic features of streptomycin have been discussed in chapter “Antibiotics”. Streptomycin sulfate remains an important drug in the treatment of tuberculosis, especially when an injectable drug is desirable, principally in individuals with severe forms of tuberculosis, e.g., meningitis, disseminated disease.
Isoniazid, introduced in 1952, is the most active drug for the treatment of tuberculosis. It is the hydrazide of isonicotinic acid. The isoniazid structure is similar to pyridoxine. Isoniazid may be bacteriostatic and bactericidal. It is active against both extracellular and intracellular organisms. Isoniazid inhibits synthesis of mycolic acids, which are essential components of mycobacterial cell walls. Isoniazid-resistant mutants occur in susceptible mycobacterial populations less frequent than streptomycin or rifampicin ones.
Isoniazid is readily absorbed from the gastrointestinal tract. It diffuses readily into all body fluids and tissues, including CNS and cerebrospinal fluid. Isoniazid crosses the placenta and is distributed into breast milk. Metabolism of isoniazid, especially acetylation by liver N-acetyltransferase, is genetically determined. The average concentration of isoniazid in the plasma of rapid acetylators is about 1/3 to 1/2 of that in slow acetylators and average half-lives are less than 1 hour and 3 hours, respectively. Patients who are slow acetylators may be more prone to development of adverse effects and may require lower doses. Isoniazid excreted by the kidneys within 24 hours; more than 90% of the isoniazid excreted as the acetylated form in fast acetylators and less than 90% in slow acetylators. The typical adult daily dose of isoniazid is 300-600 mg given 1-3 times a day. In case of serious infections or gastrointestinal disturbances it can be used i.m., i.v., or in inhalation.
Peripheral neuritis (unsteadiness, numbness, tingling, burning, or pain in hands and feet) can observed in patients, because isoniazid act as a pyridoxine (vitamin B6) antagonist, hampering the conversion of pyridoxine into its active form (see table 3.3). Pyridoxine is recommended for patients with conditions predisposing to neuropathy. CNS toxicity, which is less common, includes memory loss, psychosis, and seizures. Fever and skin rashes are occasionally seen. Diarrhea, vomiting, and hepatitis also may appear.
Ethambutol is a synthetic, bacteriostatic antitubercular agent. It diffuses into mycobacteria and suppresses multiplication by interfering with RNA synthesis. Ethambutol is well absorbed from the gut. Agent is widely distributed to most tissues and body fluids except cerebrospinal fluid. The most common serious adverse event is retrobulbar neuritis causing loss of visual acuity and red-green color blindness. This dosage-related side effect which appear after 2 months of therapy. Thus, periodic visual acuity testing is desirable. Ethambutol is contraindicated during pregnancy.
Cycloserine, a broad-spectrum antibiotic, is bactericidal for Mycobacteria. Cycloserine is an analog of the amino acid D-alanine. It inhibits bacterial cell wall synthesis. Cycloserine is rapidly and almost completely absorbed from the gastro-intestinal tract following oral administration. It is distributed widely, to most body fluids and tissues. The most serious toxic effects are peripheral neuropathy and central nervous system dysfunction, including dizziness, muscle twitching or trembling, anxiety, nervousness, drowsiness, and nightmares. These may be minimized by glutamic acid, pyridoxine, and ATP.
Kanamycin is antibiotic of aminoglycoside group. It has the same mechanism of action, spectrum activity, and pharmacokinetic as streptomycin. Kanamycin has been used for treatment of tuberculosis caused by streptomycin-resistant strains.
Ethionamide is chemically related to isoniazid. Its mechanism of action is not known exactly, but it appears also to block the synthesis of mycolic acids. It is rapidly and fully absorbed from the gastrointestinal tract following oral administration; widely distributed to most tissues and fluids. Agent may cause the intense gastric irritation, which accompanied by nausea, vomiting, loss of appetite, and abdominal pain. Orthostatic hypotension, peripheral neuritis, and skin rash can occur. Ethionamide is also hepatotoxic. Adverse effects may be alleviated by nicotinamide.
Pyrazinamide is a relative of nicotinamide. Tubercle bacilli develop resistance to pyrazinamide fairly readily. It is rapidly and completely absorbed from the gastrointestinal tract. Pyrazinamide has distributed widely, to most fluids and tissues. Major adverse effects of pyrazinamide include hepatotoxicity (in 1-5% of patients), vomiting, drug fever, and hyperuricemia, which may provoke acute gouty arthritis.
Para-aminosalicylate sodium (PASA) is structurally similar to para-aminobenzoic acid (PABA) and to the sulfanilamides. It is a folate synthesis antagonist that is active almost exclusively against Mycobacterium tuberculosis, acts bacteriostatic. It is rapidly and well absorbed from gastrointestinal tract. Agent diffuses readily into various body fluids except cerebrospinal fluid. Gastrointestinal symptoms such as anorexia, nausea, diarrhea, and epigastric pain are often accompany full doses of p-aminosalicylate sodium. Hypersensitivity reactions, hepatitis, crystalluria, granulocytopenia, goiter or myxedema may occur.
Syphilis is infectious disease caused by Treponema pallidum and transmitted by direct contact, usually through sexual intercourse. For syphilis treatment are prescribed antibiotics and organic compounds containing arsenic and bismuth.
For syphilis drugs of first choice are agents of benzylpenicillin. They possess rapid and considerable treponemocidal action. Treponema pallidum is unable to gain resistance to penicillins. In cases of allergic reactions, caused by penicillins, tetracyclines, macrolides and cephalosporins are used, though their efficiency is lower than of penicillins.
Organic arsenic-containing compound is myarsenole. Mechanism of action is the binding of arsenic with sulfhydrated groups of treponema enzymes and cessation of their activity. Because of myarsenole toxicity and the availability of many more effective agents, myarsenole current utility is limited. The adverse effects are encephalopathy, peripheral neuropathy, renal and hepatic dysfunction. Bismuth agents (biiochinole, bismoverole) have the same mechanism of action as arsenic compounds, however, bismuth compounds are less toxic. After i.m. injections they are released slowly. Adverse effects are grey gingival colour (bismuth edge), gingivitis, stomatitis, gastrointestinal disturbances, dermatitis, and renal upset. Sodium and potassium iodide are used in the late period of syphilis for enhance gummal dissimilation.