- Information
- AI Chat
T0PIC 11 TO 18 - This is the digestible pharmacology concepts from the current guidlines
Human Anatomy and Physiology (CSPE106)
University of Zimbabwe
Preview text
Antibacterial agents
Before the advent of antimicrobial agents, most diseases were considered incurable. However, with the discovery of antimicrobial agents (e. penicillin in 1928), diseases that were once deemed incurable are now treatable with only a few pills. Many infectious diseases are no longer associated with the high mortality rates they used to be. Antibacterial agents target different components in bacterial organisms, be it the cell wall or cytosolic enzymes. They can act by: 1. Inhibiting cell wall synthesis. Drugs that do this are β-lactams, carbapenems, monobactams, β-lactamase inhibitors and vancomycin. 2. Inhibiting protein synthesis. Drugs that do this are macrolides, tetracyclines, aminoglycosides and streptogramins. 3. Inhibiting DNA synthesis. These include sulphonamides and quinolones. Antibiotics can be bacteriostatic (i. prevent bacterial multiplication) or bactericidal (i. primarily kill bacteria). The distinction between bacteriostatic & bactericidal agents is not absolute, as antibacterial agents change state according to dose. Antibacterial agents also express concentration-dependent & time-dependent efficacy. Concentration-dependent efficacy is the efficacy of a drug dependent on its peak concentration relative to the minimum inhibitory concentration (MIC). Drugs with such efficacy have a strong post-antibiotic effect, i. they prevent bacterial multiplication long after the drug’s initial administration until the next drug dose. The important thing to note is that the antibiotic effect (the proportion of organisms killed) depends primarily on the actual serum level and its relation to remaining above the MIC. Examples of such drugs are quinolones and aminoglycosides. Time-dependent efficacy is the efficacy of a drug depending on the amount of time that a drug spends above the minimum inhibitory concentration (MIC), rather than the concentration itself. In other words, these drugs’ antibiotic activity is not dependent on their peak concentrations. Examples of drugs that exhibit time- dependent efficacy are penicillins and cephalosporins. The major threat to the effectiveness of antibacterial agents is the development of antibacterial resistance. This is due to adaptation of bacteria to these agents such that they either resist their action or they develop enzymes that break down the antibacterial agents. Antibiotic resistance can be minimised by rational prescribing of drugs and strict regulation of antibiotic dispensation.
B-lactams
B-lactams are antibacterial that inhibit cell wall synthesis. They all share the common property of having a 4-membered β-lactam ring bound to a second ring and a side chain. There are 5 types of β-lactam compounds: penicillins, cephalosporins, monobactams, carbapenems and β-lactamase inhibitors. These drugs share the same chemistry, mechanism of action, pharmacology and immunologic characteristics.
Penicillins
The penicillins are comprised of a β-lactam ring bound to a thiazolidine ring and a secondary amine group. The biological activity of these compounds depends on the structural integrity of the 6-aminopenicillanic acid group (β-lactam & thiazolidine rings). Classification. There are generally 4 classes of penicillins: 1. Narrow-spectrum β-lactamase-sensitive penicillins. These are also called the streptococcal penicillins. They include penicillin G/benzyl-penicillin and penicillin V/phenoxymethyl-penicillin. They have the greatest activity against Gram-positive cocci (apart from Staphylococcus aureus, which has developed resistance), some Gram-negative cocci and non-β-lactamase- producing anaerobes. They have little activity against Gram-negative rods and they are susceptible to β-lactamase. 2. Broad-spectrum β-lactamase-sensitive penicillins. These include amoxicillin and ampicillin. They have antibacterial activity against streptococci, enterococci and some Gram-negative bacteria. They have variable activity against staphylococci and are ineffective against Pseudomonas aeruginosa. Their spectrum of activity is similar to that of penicillin G, but they have wider activity against Gram-negative bacteria. However, they are less active against Gram-positive cocci than benzyl penicillin but are more active than β- lactamase resistant bacteria. 3. B-lactamase-resistant penicillins. These are also called anti-staphylococcal penicillins and include oxacillin, cloxacillin, dicloxacillin, nafcillin, flucloxacillin and methicillin. These drugs have the major advantage of being active against staphylococcus & streptococcus species, but they are ineffective against enterococci, anaerobic bacteria and Gram-negative cocci & rods. They are also less sensitive than benzyl penicillin & broad-spectrum β-lactamase-sensitive drugs against other penicillin-sensitive organisms. 4. Extended spectrum penicillins. These are also known as the anti- pseudomonas penicillins, and they include carbenicillin, ticarcillin, piperacillin and azlocillin. They have a similar spectrum of activity to broad- spectrum penicillin (Gram-positive organisms, Gram-negative cocci and anaerobic organisms), but have improved activity against Gram-negative rods, such as enterobacteriaceae, Pseudomonas and Proteus.
non-allergic skin rashes, and ampicillin is associated with pseudomembranous colitis. Penicillins – particularly benzylpenicillin – can cause convulsions when given in high doses. Some penicillins are given as sodium salts, and this should be taken into consideration when administering them to patients with renal failure. Ticarcillin deactivates aminoglycosides. Resistance. There are 4 mechanisms by which bacteria develop penicillin resistance:
- Inactivation of antibacterial agents by β-lactamase. This is the most common mechanism of resistance. Some of them are narrow in specificity – such as those produced by Staphylococcus aureus, Haemophilus influenzae and Escherichia coli – preferring penicillins to cephalosporins. Others, such as those produced by Pseudomonas aeruginosa and Enterobacter species are extended to cephalosporins as well.
- Modification of target PBPs. This is the basis of methicillin resistance in Staphylococcus aureus subtypes. It is also the basis of penicillin resistance in Pneumococci & Enterococci. These organisms produce PBPs that have low affinity for binding β-lactam antibiotics.
- Impaired penetration of drug to target PBPs. This occurs in Gram-negative organisms due to their impenetrable outer cell membranes. This membrane is absent in Gram-positive bacteria. B-lactams pass this outer cell membrane by passing through channels called porins. Drug entry can therefore be impaired by down-regulation of porins or production of an impaired protein channel. This impairment becomes important in the presence of a β- lactamase, as the drug can eventually enter the cell even if this is slow.
- Drug efflux. This is done through a pump which consists of cytoplasmic & periplasmic protein components that efficiently transport some β-lactam antibiotics from the periplasm back across the outer membrane.
Cephalosporins
Cephalosporins have a β-lactam ring bound to a dihydrothiazine ring, forming a 7- aminocephalosporanic acid nucleus. The β-lactam ring is linked to a secondary amine with a variable R-group (termed R 1 ) while the dihydrothiazine ring is linked to a different R-group (termed R 2 ). The specific drug’s R 1 group determines its antibacterial activity while the R 2 group determines the drug’s pharmacokinetics. They are similar in activity to penicillins, but are more stable to bacterial β-lactamases and therefore have a broader spectrum of activity. Cephalosporins, however, are inactive against E. coli & Klebsiella species that express β- lactamase, and they are inactive against enterococci and L. monocytogenes. They show time-dependent bacteria killing. Cephalosporins are divided into 4 generations depending mainly on the spectrum of antimicrobial activity.
First generation cephalosporins. This class includes cefazolin, ceadroxil, cephalexin, cephalothin, cephapirine and caphradine. These drugs are very active against Gram- positive cocci such as pneumococci, streptococci and staphylococci. Traditional forms are not active against methicillin-resistant Staphylococcus aureus (MRSA). The drugs are also active against a few Gram-negative bacilli – E. coli, K. pneumoniae & Proteus mirabilis. Anaerobic bacteria are also often usually sensitive except Bacteroides fragilis. All drugs except cefazolin are taken orally, and a dose of 500mg is given 4-times daily or 1g twice daily. Serum levels usually reach 15-20μg/m. Cephazolin is given intravenously usually at a dose of 0-2g every 8 hours. After infusion of 1 gram, the peak level reached is 90-120μg/ml. The drug is excreted in urine through glomerular filtration and tubular secretion, and drugs that block tubular secretion significantly increase serum levels. Oral drugs are used to treat UTIs, staphylococcal and streptococcal infections (including cellulitis & soft tissue abscesses). Cefazolin is the drug of choice in surgical prophylaxis and in infections with penicillinase-producing E. coli & Klebsiella infections. These drugs do not penetrate the central nervous system and therefore cannot treat meningitis. Second generation cephalosporins. This group includes cefaclor, cefuroxime, cefamandole, cefonicid, cefprozil, loracarbef and ceforanide. There are also structurally-similar cephamycins: cefoxitin, cefmetazole and cefotetan. These drugs have the same spectrum of activity as 1st-generation cephalosporins, but have extended coverage over Gram-negative bacteria – Klebsiella & H. influenzae and some strains of Enterobacter. They are also used to treat anaerobes, such as B. fragilis. The true 2nd-generation cephalosporins are active against H. influenzae but not serratia & B. fragillis. The cephamycins, however, are active against B. fragilis & serratia but not against H. influenzae. Second-generation cephalosporins can be taken orally or parenterally. The usual oral dosage for adults is 10-15mg/kg/day in 2- 4 divided doses. Children should be given 20-40mg/kg/day up to a maximum of 1g/day. When given intravenously, dosage varies according to the agent. The usual serum levels after infusion are 75-125μg/mL. Intramuscular injections are painful and should be avoided. Cephalosporins are cleared renally and thus they require dose adjustment in renal failure. Oral 2nd-generation cephalosporins are used to treat infections with β-lactamase-producing H. influenzae & Moraxella catarrhalis infections manifesting as sinusitis, otitis and lower respiratory tract infections. They can also be used to treat mixed anaerobic infections, such as peritonitis, diverticulitis & pelvic inflammatory disease. Cefuroxime is used to treat community-acquired pneumonia caused by H. influenzae & K. pneumoniae as well as penicillin non- susceptible pneumococci. Third generation cephalosporins. These include ceftriaxone, cefixime, ceftazidine, cefotaxime, ceftizoxime, cefoperazone, cefpodoxime, cefdinir, cefditoren and ceftibuten. These drugs have extended Gram-negative coverage and some of them can cross the blood-brain barrier. They are active against Citrobacter, S. marcescens
Other effects. At higher doses, cephalosporins cause thrombocytopaenia, haemolytic anaemia, neutropaenia, interstitial nephritis and abnormal liver function tests. Cefamandole may precipitate a disulfiram-like effect when taken with alcohol, and it may cause prothrombin deficiency.
Carbapenems
This antibiotic class is active against the widest spectrum of bacteria. Carbapenems are structurally related to penicillins in that the second ring is a 5 membered ring. The antibiotics in this class are doripenem, imipenem, ertapenem and meropenem. The drugs are bactericidal against Gram-positive & Gram-negative aerobic & anaerobic bacteria. They are resistant to most β-lactamases. They are also active against Enterobacter infections The drugs in this class are: Imipenem. This drug is active against a wide variety of microbes, including P 2. However, it is inactive against C. difficile, Enterococcus faecium and methicillin-resistant strains of Staphylococcus. It is also inactivated by tubular dehydropeptidases so that its concentrations in urine are low. It is therefore administered together with a renal dehydropeptidase inhibitor called cilastatin. The drug is indicated in septicaemia of renal origin, intra-abdominal infection and nosocomial pneumonia. Imipenem is usually given at a dose of 0.25-0 every 6- hours. Meropenem. This drug is similar to imipenem but does not have to be given together with cilastatin. It also penetrates into the CSF. It is not associated with nausea or convulsions. Meropenem is given at a dose of 0-1g every 8 hours. Carbapenems penetrate body fluids (including CSF) and they are all cleared renally. Because of their wide spectrum of action, they are generally reserved for use in ICUs, although some organisms (particularly Pseudomonas) are developing resistance against these antibiotics. Side effects are more common with imipenem than with the others. They include nausea & vomiting, diarrhoea, skin rashes, infusions site reactions and seizures in patients with renal failure 3.
Monobactams
Monobactams are a class of β-lactam antibiotics. Aztreonam is the first member of this family of antibiotics. It has a half-life of 2 hours. It is active against a wide range of Gram- negative organisms, such as Pseudomonas, Haemophilus and both Neisseria organisms (N. gonorrhoeae & N. meningitidis). Aztreonam is used to treat septicaemia and complicated urinary tract infections, as well as gonorrhoea. Adverse effects of the drug include infusion site reactions, rashes, GIT upset, hepatitis, thrombocytopaenia and neutropaenia. It has a
23 It is more active against P. aeruginosa than 3rd-generation cephalosporins. Meropenem, doripenem and ertapenem are less likely to cause seizures.
low risk of causing β-lactam allergy, and may be used with caution in patients with penicillin allergy.
Glycopeptide antibiotics
Glycopeptide antibiotics are another class of cell wall inhibitors. They inhibit cell wall synthesis by binding firmly to the D-Ala-D-Ala terminals of nascent peptidoglycan pentapeptides. This inhibits transglycosylase, and this prevents elongation & crosslinking of the peptidoglycan chain. The cell membrane is also damaged and this contributes to the antibacterial effect of the drugs. There are a number of glycopeptide antibiotics: Vancomycin. Vancomycin is the prototypical glycoside antibiotic with a molecular weight of 1500. It is bactericidal at concentrations of 0-10μg/mL, and most pathogenic staphylococci are killed by 2μg/mL or less. It is synergistic in vitro with gentamycin & streptomycin against Enterococcus faecalis & Enterococcus faecium. It is poorly absorbed and therefore given intravenously, except for when it is being used to treat pseudomembranous colitis caused by C. difficile. A 1 hour intravenous infusion of 1g produces serum levels of 15-30μg/mL for 1-2 hours. It has a half-life of 6-10 hours. CSF levels that are 7-30% of serum levels are achieved when there is meningeal inflammation. Vancomycin is indicated when there are bloodstream infections and endocarditis caused by MRSA 4. It is also used in combination with cephalosporins to treat pneumococcal meningitis. It is given as a 1g dose every 12 hours when given intravenously. For pseudomembranous colitis, vancomycin can be given at a dose of 125mg 4-times daily for 10-14 days. Teicoplanin. Teicoplanin is very similar to vancomycin in its mechanism of action & antibacterial spectrum. However, unlike vancomycin, it can be given intramuscularly as well. Teicoplanin has a long half-life of 48-72 hours. This permits once daily dosing. Telavancin. Telavancin is a semi-synthetic vancomycin derivative that is active against Gram-positive bacteria, and includes strains with reduced susceptibility to vancomycin. In addition to the normal mechanism of action shared with all the other members of this class, telavancin also disrupts the bacterial membrane potential and thus makes it more permeable. The half-life of telavancin is about 8 hours, and it is given at a dose of 10mg/kg intravenously daily. Monitoring of serum telavancin levels is not required. Telavancin is potentially teratogenic and is therefore contraindicated in pregnant women. Dalbavancin. Dalbavancin is a semi-synthetic teicoplanin derivative. It has the same mechanism of action as vancomycin & teicoplanin but has improved activity against
4 It is, however, not as effective as anti-staphylococcal penicillin.
(tetracycline, chlortetracycline & oxytetracycline; half-life = 6-8 hours), intermediate acting (demeclocycline & methacycline; half-life = 12 hours) and long-acting (doxycycline & minocycline; half-life = 16-18 hours). Tigecycline has a half-life of 36 hours. Tetracyclines are widely distributed in tissues & body fluids (except for CSF). They also cross the placenta and they can enter milk. They are metabolised by hepatic enzymes and excreted in bile (10-40%) & urine 5 (10-50%). Clinical uses. Tetracyclines are used for a wide range of bacteria. They are active against nearly all Gram-positive & Gram-negative bacteria. They are used for rickettsia (for which they are the drug of choice), Mycoplasma pneumoniae, Chlamydia and spirochetes. They are also active against H. pylori (and are therefore used to treat peptic ulcer disease caused by this organism), Vibrio species, plague, tularaemia and brucellosis. It is no longer recommended for gonococcal infections because of resistance. Tetracyclines can also be used for prophylaxis in protozoal infections, e. doxycycline in malaria (P. falciparum). Other uses include minor skin infections, MRSA and non-tuberculous Mycobacterium infections. Tigecycline is used for treatment of skin infections, intra-abdominal infections and community-acquired pneumonia. Demeclocycline can be used to treat SIADH (syndrome of inappropriate ADH secretion), as it inhibits the action of this hormone by a mechanism unrelated to its antibacterial action. Minocycline is active against N. meningitidis. Administration. The drugs can be administered orally or parenterally. The oral dose for rapidly-excreted tetracyclines (e. tetracycline hydrochloride) is 250-500mg 4- times daily for adults and 20-40mg/kg/day for children 8 years and older. For demeclocycline, the daily dose is 600mg/day (150mg 4-times daily); 100mg once or twice daily for doxycycline and 100mg twice daily for minocycline. Tetracyclines are available for intravenous infusion – 0.1-0 every 6-12 hours for most tetracyclines. Doxycycline is preferred for intravenous infusion, and it is given at 100mg every 12- 24 hours. Intramuscular injection is not recommended. Adverse effects. The adverse effects of tetracyclines are: o GIT effects. The most common are nausea, vomiting and diarrhoea. Anorexia can develop if they are taken with food. Tetracyclines can also cause opportunistic infections such as candidiasis, pseudomembranous colitis and overgrowth of Pseudomonas, Proteus, Staphylococcus, Clostridium and Candida species. Patients can also get vitamin B complex deficiencies. o Bones & teeth. Tetracyclines are readily deposited in the bones & teeth as they chelate calcium. They cause discoloration, fluorescence and enamel dysplasia in teeth, and bone deformities & growth inhibition in bones. They are therefore contraindicated in growing children & pregnant women (foetuses).
5 Doxycycline is an exception.
o Liver complications. Tetracyclines impair liver function at high intravenous doses and in pregnant women & patients with hepatic dysfunction. Hepatic necrosis has been reported at IV doses greater than 4g. o Kidney problems. Out-dated tetracycline preparations lead to renal tubular necrosis and other renal injuries, due to nitrogen retention. Normal non- expired tetracyclines can have the same effect if given with diuretics. They accumulate in patients with renal failure. o Other effects. Tetracyclines can cause venous thrombosis (when given intravenously), UV light sensitivity, dizziness and vertigo. Patients can also get vitamin B complex deficiency. Tetracycline resistance is common because of overuse of these drugs. There are 3 mechanisms that have been described through which resistance to tetracyclines comes about.
- Impaired influx or increased efflux. Increased efflux is through an active transport protein. The most affected antibiotics are tetracycline, doxycycline and minocycline. However, bacteria expressing these pumps are not resistant to tigecycline.
- Ribosome protection. The bacteria may produce proteins that interfere with the binding of tetracycline to ribosomes.
- Enzymatic inactivation.
Aminoglycosides
Aminoglycosides are protein synthesis inhibitors that, like tetracyclines, bind to the 30S subunit of ribosomes. However, unlike tetracyclines, aminoglycosides bind irreversibly to this subunit, and this makes them bactericidal rather than bacteriostatic. Aminoglycosides consist of a hexose ring – either streptidine or 2-deoxystreptamine – to which various other amino-sugars are attached. They are water-soluble and are more active at alkaline pH than at acidic pH. The prototypical aminoglycoside is streptomycin, and other examples are gentamycin, kanamycin, neomycin, amikacin, tobramycin, netilmicin, framycetin and sisomicin. Another drug that is structurally related to aminoglycosides is spectinomycin. MOA: The drug irreversibly blocks the translation of an mRNA molecule into a protein. The initial event is passive diffusion of the drug through porin channels on the bacterial outer membrane, followed by active transportation into the cytoplasm 6. Inside the cell, the drug binds to specific 30S proteins. The drug inhibits translation in 3 ways: 1. Interfering with the initiation process. 2. Causing misreading of mRNA. 3. Breaking up of polysomes into non-functional monosomes. These processes occur simultaneously and are toxic to the cell. They exhibit concentration-dependent killing. 6 Low extracellular pH & anaerobic conditions inhibit this process.
neostigmine. Other effects include hypersensitivity reactions, bone marrow suppression, haemolytic anaemia and bleeding. Resistance to aminoglycosides comes through:
- Production of a transferase enzyme that inactivates aminoglycosides by adenylation, acetylation and phosphorylation. The enzyme is obtained through plasmid acquisition.
- Altered permeation or transport.
- Deletion or alteration of the receptor protein on the 30S subunit.
50S inhibitors
These antibiotics inhibit the large subunit of bacterial ribosomes. They include macrolides, chloramphenicol, clindamycin and streptogramins.
Macrolides
Macrolides are a group of antibiotics characterised by a macro-cyclic lactone ring to which deoxy-sugars are attached. The prototypical drug is erythromycin, and the other members of the class (clarithromycin, azithromycin, spiramycin and telithromycin – a ketolide) are derived from it. Macrolides are bactericidal and they exhibit time-dependent killing. Erythromycin. Erythromycin was obtained in 1952 from Streptomyces erytheus. It consists of a macrolide ring with desosamine & cladinose sugars. It is poorly soluble in water, so it is normally dispensed in the form of esters & salts. Its activity is also increased at alkaline pH. o MOA: Erythromycin inhibits protein synthesis by binding to the 50S rRNA. This site is near the peptidyl-transferase centre and therefore inhibits chain elongation by blocking the polypeptide exit tunnel. This leads to dissociation of the aminoacyl-tRNA molecule from the ribosome. Erythromycin also inhibits the formation of rRNA. Macrolides concentrate in phagocytes, thus enhancing phagocyte-mediated killing of bacteria. o Pharmacokinetics: Erythromycin is basic and is therefore destroyed by stomach acid. It is therefore usually administered with an enteric coat. Food interferes with absorption of the drug. An oral dosage of 2g/d produces serum concentrations of 2μg/mL. A 500mg intravenous dose produces serum concentrations of 10μg/ml 1 hour after infusion. The serum half-life is 1 hours (5 hours in anuric patients). The dose is not adjusted in renal failure patients, and haemodialysis does not remove the drug. The drug is distributed widely in tissues, except the brain & CSF. Large amounts of the drug are excreted in bile, and 5% of the drug is excreted in urine. The drug is taken up by PMN leukocytes & macrophages and it traverses the placenta.
o Uses: Erythromycin is the drug of choice in Corynebacteria infections, such as diphtheria, erythrasma and corynebacterial sepsis. It is also used in respiratory, neonatal, ocular and genital Chlamydia infections and it is used in community- acquired pneumonia caused by M. pneumoniae and L. pneumophila. It can also substitute penicillin for treatment of staphylococcal, streptococcal & pneumococcal infections in patients with penicillin allergies. It has also been recommended as prophylaxis against bacterial endocarditis for dental procedures. Erythromycin is sometimes combined with kanamycin or neomycin for colonic surgery preparation. o Dosage: Erythromycin can be administered as a stearate, estolate or salt. The estolate is the best absorbed form as it is resistant to hydrolysis in the stomach. Regardless of form, the dosage is the same – 250-500mg every 6 hours (4-times daily) in adults, and 40mg/kg/d for children. The dosage for erythromycin ethylsuccinate is 400-600mg per 6 hours. Erythromycin can also be administered as an intravenous preparation, and this is usually in the form of erythromycin gluceptate or lactobionate. This is 500-1000mg every 6 hours for adults and 20- 40mg/kg/d for children. o Adverse effects: The adverse effects are mostly GIT-related: anorexia, vomiting & diarrhoea, cholestatic jaundice & hepatitis. Erythromycin also inhibits cytochrome P450 enzymes, and thus it increases serum concentration of numerous drugs, such as warfarin, cyclosporine and methyl-prednisone. Stearates & esters have a lower risk of side effects. There is partial cross- resistance between erythromycin & clindamycin. Clarithromycin. Clarithromycin is derived from erythromycin by addition of a methyl group. It has improved oral bioavailability & acid stability. It has the same mechanism of action as erythromycin. It also has the same microbacterial action, except that it is more active against Mycobacterium avium complex. It also has activity against M. leprae, Toxoplasma gondii and H. influenzae. Erythromycin- resistant bacteria are also resistant to clarithromycin. It has a longer half-life of 6 hours, and this permits twice-daily dosing. The half-life increases with the dose. A 500mg dose will produce serum concentrations of 2-3μg/mL. The recommended formulation is 250-500mg twice daily. It is metabolised in the liver. It has lower incidence of GIT side effects. Azithromycin. Azithromycin is derived from erythromycin by introduction of a methylated nitrogen into the lactone ring. It has similar MOA, spectrum of activity and clinical uses as clarithromycin. It is, however, slightly less active against staphylococci & streptococci than erythromycin & clarithromycin. It produces relatively lower serum concentrations (0μg/mL) than the other drugs in its group. It penetrates tissues well, with tissue concentrations greatly exceeding serum concentrations. It is released slowly from tissues such that its elimination half-life is close to 3 days. It does not have the drug interactions that clarithromycin &
Chloramphenicol
Chloramphenicol is a neutral stable compound that is a broad-spectrum antibiotic. Crystalline chloramphenicol is soluble in alcohol but poorly soluble in water. However, chloramphenicol succinate is readily soluble in water. MOA: Chloramphenicol binds reversibly to the 50S subunit of bacterial ribosomes and inhibits peptide bond formation by blocking the action of peptidyl-transferase. It is bacteriostatic 10. It also inhibits mitochondrial protein synthesis in the mammalian bone marrow. Pharmacokinetics: After oral administration, crystalline chloramphenicol is rapidly & completely absorbed. The normal blood levels after a 1g oral dose are 10-15μg/mL. Chloramphenicol succinate, which is the parenteral formulation, is hydrolysed to free chloramphenicol and it gives a lower serum level. It has a half-life of about 2 hours. Chloramphenicol is widely distributed to all tissues & body fluids, including the brain & CSF (even in the absence of meningeal inflammation). Chloramphenicol is inactivated by conjugation with glucuronic acid in the liver 11 or by reduction to inactive aryl amines. Active chloramphenicol (10%) and its inactive metabolites (90%) are excreted in urine, while a small amount is excreted in bile & faeces. Clinical uses: Chloramphenicol is now rarely used due to its side effects, bacterial resistance and the availability of many other effective alternatives. It is considered in treatment of rickettsia infections, and it can be used as an alternative to β-lactam antibiotics in the treatment of bacterial meningitis. It can also be used to treat eye infections, but is ineffective against chlamydial infections. It is also effective against infections with the Salmonella species, H. influenzae and meningococcal & pneumococcal CNS infections. Dosage: The usual dosage of chloramphenicol is 50-100mg/kg/d. This is usually given in 4 divided doses. The dosage need not be altered in renal failure, but needs to be reduced markedly in hepatic failure. In neonates, the dosage needs to be reduced to 25mg/kg/d. Adverse effects: GIT disturbances (nausea, vomiting & diarrhoea) are occasional. Oral & vaginal candidiasis can occur. It commonly causes a dose-related suppression of red cell synthesis. Aplastic anaemia is an idiosyncratic reaction unrelated to the dose and it occurs in 1 in 24 000-40 000. It tends to be irreversible & fatal. Chloramphenicol also inhibits hepatic enzymes, and this leads to raised serum concentrations of many drugs, e. warfarin, phenytoin, tolbutamide and chlorpropamide. New born infants may develop grey baby syndrome due to accumulation of the drug. Babies present with vomiting, flaccidity, hypothermia, grey colour, shock and vascular collapse. The condition carries a mortality of 40%.
Streptogramins
1011 It is, however, bactericidal against H. influenzae, N. meningitidis and S. pneumoniae. This process is less effective in neonates.
Streptogramins are bactericidal drugs that work by inhibiting the 50S ribosomal subunit. The drugs in this class are quinupristin (streptogramin B) and dalfopristin (streptogramin A). These drugs are usually administered as a combination. MOA: The 2 drugs bind to the same site as macrolides & clindamycin and therefore have the same effect (this also renders them bactericidal). They inhibit binding of amniocyl-tRNA molecules to the ribosome and therefore inhibit chain elongation. Pharmacokinetics: The drugs are administered intravenously. Peak serum concentrations after an hour are 3μg/mL for quinupristin and 7μgmL for dalfopristin. They are rapidly metabolised by the liver and have a half-life of 0 & 0 hours respectively. They are primarily eliminated through bile. Uses: The drugs are active against infections by staphylococci and vancomycin- resistant strains of E. faecium (but not E. faecalis). They are also active against other Gram-positive organisms. They are generally reserved for patients with infections that are resistant to most antibiotic classes, such as MRSA, vancomycin-resistant enterococci and penicillin-resistant S. pneumoniae. Most Gram-negative organisms have impermeable membranes and are therefore resistant. However, Legionella pneumophila & Mycoplasma pneumoniae are susceptible. Dosage: The drugs are usually administered as a combined preparation of quinupristin-dalfopristin at a ratio of 30%:70%. It is administered intravenously at a dose of 7/kg every 8-12 hours. Dose adjustment is not necessary for renal impairment, haemodialysis or peritoneal dialysis. However, patients with hepatic insufficiency may not tolerate the drug at its usual dosage. The dosage may then be reduced to 7/kg every 12 hours or 5mg/kg every 8 hours. Adverse effects: The adverse effects of streptogramins are most infusion-related: venous irritation 12 , arthralgia & myalgia and infusion pain. Patients may also develop hyperbilirubinaemia.
Nucleic acid synthesis inhibitors
The nucleic acid synthesis inhibitors include sulphonamides, quinolones and azoles.
Sulphonamides
Sulphonamides are antibacterial compounds that have a sulphanilamide nucleus. This nucleus is structurally similar to ρ-aminobenzoic acid (PABA). Various sulphonamides are formed by substitution into the amido group or the amine group of the sulphanilamide nucleus. The different sulphonamide compounds are sulfamethoxazole, sulfadiazine, sulfamethizole, sulfadoxine, sulphpyridine and sulfasalazine. Sulphonamides are more soluble at alkaline than at acidic pH. They can also be prepared as sodium salts that can be administered as intravenous drugs.
12 This can be minimised by inserting the drug through a central line.
fever, skin rashes, exfoliative dermatitis, photosensitivity, urticaria, GIT disturbances (nausea, vomiting & diarrhoea) and Stevens-Johnson syndrome. They can also cause Lyell syndrome (toxic epidermal necrosis). Sulphonamides may precipitate in urine and produce crystalluria, haematuria or even obstruction; this can cause acute renal failure. They can also cause haemolytic (in patients with G6PD deficiency) or aplastic anaemia, granulocytopaenia, thrombocytopaenia and leukemoid reactions. They can cause methaemoglobinaemia, which may cause cyanosis. If taken by pregnant women they can cause kernicterus in the foetus as well as folate deficiency (particularly cotrimoxazole) which could be teratogenic.
Quinolones
Quinolones are fluorinated analogues of nalidixic acid. Examples of quinolones are ciprofloxacin, levofloxacin and norfloxacin. They developed because of their excellent activity against Gram-negative bacteria. Earlier agents had reduced activity against Gram- positive cocci, but newer agents have improved coverage. MOA: Quinolones block bacterial DNA synthesis by inhibiting bacterial topo- isomerase II, also known as DNA gyrase, and topo-isomerase IV. DNA gyrase lead to relaxation of the positively-supercoiled double-stranded bacterial DNA, and this allows transcription & translation. Topo-isomerase IV leads to separation of replicated DNA into the respective daughter cells. The drugs are initially bacteriostatic, but become bactericidal when the bacteria can no longer repair their DNA. They exhibit concentration-dependent killing. Pharmacokinetics: When orally taken, quinolones are well-absorbed, although this absorption is interfered by divalent & trivalent cations 14. They have a bioavailability of 80-95%. The half-lives of the drugs vary from 3 to 10 hours. The serum concentrations of the drugs are generally the same, whether taken orally or intravenously. Quinolones are distributed widely in tissues & body fluids. Most quinolones are eliminated in urine (except moxifloxacin), either by glomerular filtration or tubular secretion. Clinical uses: There are four generations of quinolones, and this is based on their activity against Gram-positive organisms. o First generation quinolones. The first generation quinolones are nalidixic acid & cinofloxacin. They have limited Gram-negative activity. They have no systemic effects, and they are used to treat bladder & GIT infections. o Second generation quinolones. The second-generation quinolones includes norfloxacin, ciprofloxacin, ofloxacin, enoxacin, lomefloxacin and pefloxacin. Norfloxacin has the lowest activity of all fluoroquinolones on both Gram- positive & Gram-negative organisms. Ciprofloxacin has the greatest activity against Gram-negative organisms, particularly against P. aeruginosa.
14 For this reason, the drug should be taken 2 hours before or 4 hours after a meal.
Generally, 2nd-generation agents have excellent Gram-negative activity and moderate Gram-positive activity. MRSA is resistant to these agents, o Third generation quinolones. This group includes levofloxacin, sparfloxacin and gatilofloxacin. These agents have improved activity against Gram- positive organisms. Levofloxacin is the L-isomer of ofloxacin and has superior activity than ciprofloxacin against Gram-positive organisms, including Streptococcus pneumoniae. o Fourth generation quinolones. This group includes moxifloxacin, gemifloxacin and travofloxacin. These agents have even greater Gram- positive coverage (particularly S. pneumoniae & some staphylococci), and they also have good activity against anaerobes. However, none of these agents is as active as ciprofloxacin against Gram-negative organisms. Quinolones are also used to treat atypical pneumonia caused by agents such as Mycoplasma & Chlamydia, and infections caused by intracellular pathogens such as M. tuberculosis & M. avium complex. Dosages: The oral doses vary according to the drug used. Ciprofloxacin is given at a dose of 500mg orally twice daily while levofloxacin is given at a dose of 500mg orally once or twice daily. Gemifloxacin is given at a dose of 320mg. Otherwise, the rest are administered at doses of 400mg orally once daily. Dose adjustment is required in renal failure. Adverse effects: The adverse effects of quinolone use include GIT effects (nausea, vomiting and diarrhoea) and occasional headaches, dizziness, insomnia, skin rash and abnormal liver function tests. Convulsions have also occurred during treatment, and they can also cause confusion. Other effects include QT prolongation, hyperglycaemia in diabetics and hypoglycaemia in patients on oral hyperglycaemic agents 15 , tendonitis and peripheral neuropathy. Some quinolones are potent enzyme inhibitors and therefore inhibit metabolism of some drugs such as warfarin, theophylline and sulfonylureas.
Principles of use of antibiotics
The use of antibiotics in hospitals & clinical settings nowadays is guided by national guidelines on antibiotic use. Many conditions now have defined antibiotic regimens applied to them. This serves to achieve reasonable economy with antibiotic production & use as well as to reduce the development of resistance in organisms. Before selecting a drug, the clinician needs to understand the patient he/she is dealing with, and the causative organism. Patient factors include patient age, sex (and pregnancy status if female), history of allergy, renal & hepatic function, immune status (in case of those with HIV or on immunosuppressive therapy), ability to tolerate drugs by mouth, severity of disease and presence of other medications. The known organism has a range of 15 This was seen with gatifloxacin.
T0PIC 11 TO 18 - This is the digestible pharmacology concepts from the current guidlines
Course: Human Anatomy and Physiology (CSPE106)
University: University of Zimbabwe
- Discover more from:
