دکتر فرينبز راشذ مرنذی متخصص آسيب شنبسی تشريحی و ببلينی عضو هيئت علمی آزمبيشگبه مرجع سالمت

Antibiotical grouping Mechanisms of action Bacteriostatic Bacteriocidal Site of action

Antibiotics Antibiotics and vaccines are among the biggest medical advances since 1000. (Culver Pictures) For lecture only BC Yang

Thanks to work by Alexander Fleming (1881-1955), Howard Florey ( 1898-1968) and Ernst Chain (1906-1979), penicillin was first produced on a large scale for human use in 1943. At this time, the development of a pill that could reliably kill bacteria was a remarkable development and many lives were saved during World War II because this medication was available. A. Fleming E. Chain H. Florey For lecture only BC Yang

Penicillin: an extensively studied example For lecture only BC Yang

A tale by A. Fleming He took a sample of the mold from the contaminated plate. He found that it was from the penicillium family, later specified as Penicillium notatum. Fleming presented his findings in 1929, but they raised little interest. He published a report on penicillin and its potential uses in the British Journal of Experimental Pathology. For lecture only BC Yang

Antibiotic Grouping 1. ß-lactamase (penicillin,cephem,penem,monobactam, ß- lactam- ß-lactamase inhibitor 2. Aminoglycosides 3. Glycopeptides 4. Macrolides 5. Tetracyclines 6. Quinolones 7. Folate pathway inhibitors 8. Lipopeptides 9. Single drug class

Mechanism of Action Antibiotic action can be split into 2 mechanisms: Bacteriostatic Bacteriocidal

Bacteriostatic Bacteriostatic antibiotics inhibit growth and reproduction of bacteria without killing them. Bacteriostatic agents must work with the immune system to remove the microorganisms from the body. Bacteriostatic antibiotics hamper the growth of bacteria by interfering with bacterial: Protein production DNA replication Cellular metabolism

Bacteriostatic Antibiotics tetracyclines sulphonamides spectinomycin trimethoprim chloramphenicol macrolides lincosamides

Bacteriocidal A bacteriocide is a substance that kills the bacteria of choice and, preferably, nothing else. Microbe death is usually achieved by disruption of the bacterial cell membrane leading to lysis.

Bactericidal antibiotics Bactericidal antibiotics Bactericidal antibiotics kill bacteria; bacteriostatic antibiotics only slow their growth or reproduction. Penicillin is a bactericide, as are cephalosporins, all belonging to the group of β-lactam antibiotics. They act in a bactericidal manner (by disrupting cell wall precursor leading to lysis). Aminoglycosidic antibiotics are usually considered bactericidal, although they may be bacteriostatic with some organisms. They act by binding irreversibly to 30s ribosomal subunit, reducing translation fidelity leading to inaccurate protein synthesis). The other effect is the inhibition of protein synthesis due to premature separation of the complex between mrna and ribosomal proteins. The final result is bacterial cell death. Other bactericidal antibiotics include the fluoroquinolones, nitrofurans, vancomycin, monobactams, co-trimoxazole, and metronidazole.

β-lactams β-lactam antimicrobial agents all share the common, central, four-member β-lactam ring and the principal mode of action of inhibition of cell wall synthesis. Additional ring structures or substituent groups added to the β-lactam ring determine whether the agent is classified as a penicillin, cephem, carbapenem, or monobactam.

β-lactam/β-lactamase Inhibitor Combinations These antimicrobial agents are combinations that include a penicillin class antimicrobial agent and a second agent that has minimal antibacterial activity, but functions as an inhibitor of some lactamases.currently, three β-lactamase inhibitors are in use: clavulanic acid, sulbactam, and tazobactam. The results of tests of only the penicillin portion of the combination against β-lactamase-producing organisms are often not predictive of susceptibility to the twodrug combination.

Glossary I (Part 1). β-lactams: Class and Subclass Designation and Generic Name Agents Included; Generic Names Antimicrobial Subclass Antimicrobial Class penicillin penicillin a penicillins amoxicillin aminopenicillin a ampicillin azlocillin ureidopencillin a mezlocillin piperacillin carbenicillin carboxypenicillin a ticarcillin cloxacillin penicillinase-stable dicloxacillin penicillins b methicillin nafcillin oxacillin mecillinam amoxicillin-clavulanic acid ampicillin-sulbactam piperacillin-tazobactam ticarcillin-clavulanic acid cefazolin cephalothin cephapirin cephradine cefamandole cefonicid cefuroxime (sodium) cefoperazone cefotaxime ceftazidime ceftizoxime ceftriaxone cefepime cefmetazole cefotetan cefoxitin moxalactam cefaclor cefadroxil cefdinir cefditoren cefetamet cefixime cefpodoxime cefprozil ceftibuten cefuroxime (axetil) cephalexin cephradine loracarbef aztreonam doripenem ertapenem imipenem amidinopenicillin cephalosporin I c,e cephalosporin II c,e cephalosporin III c,e cephalosporin IV c,e cephamycin d oxacephem cephalosporin e carbacephem carbapenem β-lactam/β-lactamase inhibitor combinations cephems (parenteral) cephems (oral) monobactams penems

Penicillin Penicillin is one of the earliest discovered and widely used antibiotic agents, derived from the Penicillium mold. In 1928, Sir Alexander Fleming observed that colonies of the bacterium Staphylococcus aureus could be destroyed by the mold Penicillium notatum, proving that there was an antibacterial agent present.

Penicillins These penicillins are penicillinase-labile;hydrolyzed by staphylococcal penicillinase penicillin penicillin Penicillins amoxicillin aminopenicillin azlocillin mezlolin piperacillin ureidopencillin carbenicillin ticarcillin carboxypenicillin

Penicillinase-stable penicillin Penicillinase-stable penicillin Cloxacillin Dicloxacillin Meticillin Nafcillin oxacillin

ß- lactam /ß- lactamase inhibitor combinations ß- lactam /ß- lactamase inhibitor combinations amoxicillin-clavulanic acid ampicillin-sulbactam piperacillintazobactam ticarcillin-clavulanic acid

Antibiotic class Antibacterial Effect & Mechanism of action Bacteria Mechanism β lactams penicillins beta-lactamase G+ Some non producing fastidious aerobic G- some anaerobic bacteria Inhibition of cell wall synthesis β lactamsβ lactamase inhibitors β lactamase producing bacteria

Sites of action For lecture only BC Yang

cephems The cephalosporins are a class of β-lactam antibiotics. Together with cephamycins (cephmetazole,cefotetan,cefoxitin) they constitute a subgroup of β-lactam antibiotics called cephems.

Cephems cefazolin cephalothin cephapirin cephradine cefamandole cefonicid cefuroxime (sodium) cefoperazone cefotaxime ceftazidime ceftizoxime ceftriaxone cefepime cefmetazole cefotetan cefoxitin moxalactam cefaclor cefadroxil cefdinir cefditoren cefetamet cefixime cefpodoxime cefprozil ceftibuten cefuroxime (axetil) cephalexin cephradine cephalosporin I c,e cephalosporin II c,e cephalosporin III c,e cephalosporin IV c,e cephamycin d oxacephem cephalosporin e cephems (parenteral) cephems (oral) III and IV are also referred to as extended-spectrum cephalosporins. This does not imply activity against ESBL-producing gram-negative bacteria.

Cephems (Including Cephalosporins) Different cephem antimicrobial agents exhibit somewhat different spectrums of activity against aerobic and anaerobic gram-positive and gram-negative bacteria.

The cephem antimicrobial class classical cephalosporins, as well as the agents in subclasses cephamycin, oxacephem, and carbacephems Cephalosporins are often referred to as first-, second-, third-, or fourthgeneration cephalosporins, based on the extent of their activity against the more antimicrobial agent-resistant, gram-negative aerobic bacteria. Not all representatives of a specific group or generation necessarily have the same spectrum of activity. Because of these differences in activities, representatives of each group may be selected for routine testing.

Antibacterial Effect & Mechanism of action Antibiotic class Bacteria Mechanism Aerobic & anaerobic g+,gcephems(cephalosporins, cephamycin,oxacephem, carbacephem)

Penems The penem antimicrobial class which includes two subclasses, the carbapenems and penems, differs slightly in structure from the penicillin class; agents in this class are much more resistant to β-lactamase hydrolysis, which provides them with broad-spectrum activity against many gram-positive and gram-negative bacteria.

Antibacterial Effect & Mechanism of action Antibiotic class Bacteria Mechanism )Carbapenem,penem) Penems Broad spectrum activity against many aerobic g+,g-

Monobactams Monobactam antimicrobial agents are monocyclic β-lactams. At present, aztreonam (which has activity Only against aerobic gramnegative bacteria) is the only monobactam antimicrobial agent approved for use by the FDA.

Antibacterial Effect & Mechanism of action Antibiotic class Bacteria Mechanism monobactam Only against aerobic gram +

Glycopeptides Glycopeptide antimicrobial agents, which include vancomycin and teicoplanin, share a complex chemical structure and a principal mode of action of inhibition of cell wall synthesis at a different site than that of The β-lactams. The activity of this group is directed primarily at aerobic gram-positive bacteria. Vancomycin is an accepted agent for treatment of a grampositive bacterial infection in the penicillin-allergic patient, and it is useful for therapy of infections due to β-lactamresistant, gram-positive bacterial strains (e.g., methicillinresistan Staphylococcus aureus (MRSA) and some enterococci).

Aminoglycosides Aminoglycosides are structurally related antimicrobial agents that inhibit bacterial protein synthesis at the ribosomal level. This class includes agents variously affected by aminoglycoside-inactivating enzymes,resulting in some differences in the spectrum of activity among the agents. Aminoglycosides are used primarily to treat aerobic, gramnegative rod infections or in synergistic combinations with cell-wall- active antimicrobial agents (e.g., penicillin, ampicillin, vancomycin) against some resistant, gram-positive bacteria, such as enterococci.

Macrolides Macrolides are structurally related antimicrobial agents that inhibit bacterial protein synthesis at the ribosomal level. Several members of this class currently in use may need to be considered for testing against fastidious, gram-negative bacterial isolates. For gram-positive organisms, only erythromycin needs to be tested routinely. The antimicrobial spectrum of macrolides is slightly wider than that of penicillin, and therefore macrolides are a common substitute for patients with a penicillin allergy.

Common antibiotic macrolides Azithromycin (Zithromax, Zitromax, Sumamed) - Unique, does not inhibit CYP3A4 Clarithromycin (Biaxin) Dirithromycin (Dynabac) Erythromycin Roxithromycin (Rulid, Surlid,Roxid)

Tetracyclines Tetracyclines are structurally related antimicrobial agents that inhibit protein synthesis at the ribosomal level of certain gram-positive and gram-negative bacteria. Agents in this group are closely related and, with few exceptions, only tetracycline may need to be tested routinely. Organisms that are susceptible to tetracycline are also considered susceptible to doxycycline and minocycline. However, some organisms that are intermediate or resistant to tetracycline may be susceptible to doxycycline or minocycline or both.

Tetracyclines Tetracyclines are a group of broad-spectrum antibiotics whose general usefulness has been reduced with the onset of bacterial resistance. Despite this, they remain the treatment of choice for some specific indications. They are so named for their four ( tetra- ) hydrocarbon rings ( -cycl- ) derivation ( -ine ). More specifically, they are defined as "a subclass of polyketides having an octahydrotetracene-2-carboxamide skeleton".they are collectively known as "derivatives of polycyclic naphthacene carboxamide".

Tetracyclines The 4 rings of the basic tetracycline structure

Quinolones Quinolones (quinolones and fluoroquinolones) are structurally related antimicrobial agents that function primarily by inhibiting the DNAgyrase or topoisomerase activity of many gram-positive and gram-negative bacteria. Some differences in spectrum may require separate testing of the individual agents.

Folate Pathway Inhibitors Sulfonamides and trimethoprim are chemotherapeutic agents with similar spectra of activity resulting from the inhibition of the bacterial folate pathway Sulfisoxazole is among the most commonly use sulfonamides in the treatment of urinary tract infections; thus, it may be the appropriate selection for in vitro testing. Sulfamethoxazole is usually tested in combination with trimethoprim, because these two antimicrobial agents inhibit sequential steps in the folate pathway of some gram-positive and gramnegative bacteria.

Sulfonamides There are several sulfonamide-based groups of drugs. The original antibacterial sulfonamides (sometimes called simply sulfa drugs) are synthetic antimicrobial agents that contain the sulfonamide group. Some sulfonamides are also devoid of antibacterial activity, e.g., the anticonvulsant sultiame. The sulfonylureas and thiazide diuretics are newer drug groups based on the antibacterial sulfonamides. Sulfa allergies are common, hence medications containing sulfonamides are prescribed carefully. It is important to make a distinction between sulfa drugs and other sulfur-containing drugs and additives, such as sulfates and sulfites, which are chemically unrelated to the sulfonamide group, and do not cause the same hypersensitivity reactions seen in the sulfonamide

Trimethoprim Trimethoprim is a bacteriostatic antibiotic mainly used in the prophylaxis and treatment of urinary tract infections. Trimethoprim was commonly used in combination with sulfamethoxazole, a sulfonamide antibiotic, which inhibits an earlier step in the folate synthesis pathway (see diagram above). This combination, also known as co-trimoxazole, TMPsulfa, or TMP-SMX, results in an in vitro synergistic antibacterial effect by inhibiting successive steps in folate synthesis. This claimed benefit was not seen in general clinical use.its use has been declining due to reports of sulfamethoxazole bone marrow toxicity, resistance and lack greater efficacy in treating common urine and chest infections, and side effects of antibacterial sulfonamides. As a consequence, the use of co-trimoxazole was restricted in1995.

Sulfonamides The structure of the sulfonamide group

Lipopeptides Lipopeptides are a structurally related group of antimicrobial agents, whose principal target is the cell membrane. The polymyxin subclass, which includes polymyxin B and colistin, has activity against gramnegative organisms. Daptomycin is a cyclic lipopeptide with activity against gram-positive organisms. Lipopeptide activity is strongly influenced by the presence of divalent cations in the medium used to test them. The presence of excess calcium cations inhibits the activity of the polymyxins, whereas the presence of physiologic levels (50 mg/l) of calcium ions is essential for the proper activity of daptomycin.

Antibiotic class Antibacterial Effect & Mechanism of action Bacteria Mechanism Glycopeptide(vancomycin, teicoplanin) Primarily aerobic g+ Inhibition of cell wall synthesis Aminoglicosides Macrolides Primarily g-rods,synergistic combination with cell wall active drugs(pen,amp,van) against resistant g+ bacteria fastidious g-.for G+ only erythrmycin need to be tested. Inhibit protein synthesis at ribosomal level Inhibit protein synthesis at ribosomal level Tetracyclines G +, G- Inhibit protein synthesis at ribosomal level Quinolones(quinolones,flu G +, G- Inhibiting DNA gyrase or

Antibiotic class Sulfonamide /trimetoprim Folate pathway inhibitors Lipopeptide Single Drug class chloramphenicol clindamycin Linezolid streptogramins telitromycin tigecycline rifampin nitrofurantoin Antibacterial Effect & Mechanism of action G+,G- Bacteria G-(polymyxin B,colistin) G+ Daptomycin Mechanism Inhibition of folate pathway Cell membrane Inhibit protein synthesis Inhibit protein synthesis Inhibit protein synthesis Inhibit protein synthesis Inhibit protein synthesis Inhibit protein synthesis RNA synthesis inhibitors Inhibit protein synthesis at ribosomal level

Single-Drug Classes The following antimicrobial agents (antimicrobial class) are currently the only members of their respective classes used in humans that are included in this document, and are appropriate for in vitro testing. These include chloramphenicol (phenicols), clindamycin (lincosamides), linezolid (oxazolidinones), quinupristin-dalfopristin (streptogramins), telithromycin (ketolides), tigecycline (glycylcyclines), all of which inhibit protein synthesis, and rifampin (ansamycins), which is an RNA synthesis inhibitor. Nitrofurantoin (nitrofurans), which is used only in the therapy of urinary tract infections, acts by inhibiting several protein synthesis-and-assembly steps at the ribosomal level. Fosfomycin (fosfomycins), also approved by the FDA for urinary tract infections, inhibits enzymes involved in cell wall synthesis.

Chloramphenicol Chloramphenicol is a bacteriostatic antimicrobial originally derived from the bacterium Streptomyces venezuelae, isolated by David Gottlieb, and introduced into clinical practice in 1949. It was the first antibiotic to be manufactured synthetically on a large scale. Chloramphenicol is effective against a wide variety of microorganisms; it is still very widely used in low income countries because it is exceedingly inexpensive, but has fallen out of favour in the West due to a very rare but very serious side effect: aplastic anemia. In the West, the main use of chloramphenicol is in eye drops or ointment for bacterial conjunctivitis. Chloramphenicol has recently been discovered to be a life saving cure for chytridiomycosis in amphibians. Chytridiomycosis is a fungal disease that has been blamed for the extinction of one-third of the 120 frog species lost since 1980.

Sites of action For lecture only BC Yang