CEPHALOSPORINS

1. Introduction Antibacterial agents which inhibit bacterial cell wall synthesis Discovered from a fungal colony in Sardinian sewer water (1948) Cephalosporin C identified in 1961

6. Mechanism of Action The acetoxy group acts as a good leaving group and aids the mechanism

The Cephalosporins Generation Parenteral Agents Oral Agents First-generation Cefazolin Cefadroxil, cephalexin Second-generation Cefotetan, cefoxitin, cefuroxime Cefaclor, cefprozil, cefuroxime axetil, loracarbef Third-generation Cefotaxime, ceftazidime, ceftizoxime, ceftriaxone Cefdinir, cefditoren, cefpodoxime proxetil, ceftibuten, cefixime Fourth-generation Cefepime

8. First Generation Cephalosporins Cephalothin First generation cephalosporin More active than penicillin G vs. some Gram -ve bacteria Less likely to cause allergic reactions Useful vs. penicillinase producing strains of S. aureus Not active vs. Pseudonomas aeruginosa Poorly absorbed from GIT Administered by injection Metabolised to give a free 3-hydroxymethyl group (deacetylation) Metabolite is less active

8. First Generation Cephalosporins Cephalothin - drug metabolism Metabolism Less active OH is a poorer leaving group Strategy Replace the acetoxy group with a metabolically stable leaving group

8. First Generation Cephalosporins Cephaloridine The pyridine ring is stable to metabolism The pyridine ring is a good leaving group (neutralisation of charge) Exists as a zwitterion and is soluble in water Poorly absorbed through the gut wall Administered by injection

8. First Generation Cephalosporins Cefalexin The methyl group at position 3 is not a good leaving group The methyl group is bad for activity but aids oral absorption - mechanism unknown Cefalexin can be administered orally A hydrophilic amino group at the a-carbon of the side chain helps to compensate for the loss of activity due to the methyl group

First Generation Cephalosporins Cefazolin Cefadroxil Cefalexin

First Generation Cephalosporins include Cefazolin (parenteral) as well as cefadroxil and cephalexin (oral). Gram-positive bacteria Streptococcus pyogenes, Some virdans streptococci, Some Staphylococcus aureus, Some Streptococcus pneumoniae Gram-negative bacteria Some Eschericia coli, Some Klebsiella pneumoniae, Some Proteus mirabilis

9. Second Generation Cephalosporins 9.1 Cephamycins Cephamycin C Isolated from a culture of Streptomyces clavuligerus First b-lactam to be isolated from a bacterial source Modifications carried out on the 7-acylamino side chain

9. Second Generation Cephalosporins 9.1 Cephamycins Cefoxitin Broader spectrum of activity than most first generation cephalosporins Greater resistance to b-lactamase enzymes The 7-methoxy group may act as a steric shield The urethane group is stable to metabolism compared to the ester Introducing a methoxy group to the equivalent position of penicillins (position 6) eliminates activity.

9. Second Generation Cephalosporins 9.2 Oximinocephalosporins Cefuroxime Much greater stability against some b-lactamases Resistant to esterases due to the urethane group Wide spectrum of activity Useful against organisms that have gained resistance to penicillin Not active against P. aeruginosa Used clinically against respiratory infections

Second generation The second-generation cephalosporins have a greater Gram-negative spectrum while retaining some activity against Gram-positive cocci. They are also more resistant to beta-lactamase. Cefaclor (Ceclor, Distaclor, Keflor, Raniclor) Cefonicid (Monocid) Cefprozil (cefproxil; Cefzil) Cefuroxime (Zinnat, Zinacef, Ceftin, Biofuroksym) Cefuzonam

Forms of Cefuroxime (2nd generation cephalosporin) (ZINACEF) Cefuroxime axetil (CEFTIN)

The Second-generation cephalosporins include Cefotetan, cefoxitin, and cefuroxime (all parenteral) as well as Cefaclor, cefprozil, cefuroxime axetil, and loracarbef (all oral). Gram-positive bacteria True cephalosporins have activity equivalent to first-generation agents. Cefoxitin and cefotetan have little activity Gram-negative bacteria Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Haemophilus influenzae, Neisseria spp. Anaerobic bacteria Cefoxitin and cefotetan have moderate anaerobic activity.

10. Third Generation Cephalosporins Oximinocephalosporins Aminothiazole ring Aminothiazole ring enhances penetration of cephalosporins across the outer membrane of Gram -ve bacteria May also increase affinity for the transpeptidase enzyme Good activity against Gram -ve bacteria Variable activity against Gram +ve cocci Variable activity vs. P. aeruginosa Lack activity vs MRSA Generally reserved for troublesome infections

10. Third Generation Cephalosporins Oximinocephalosporins Ceftazidime Injectable cephalosporin Excellent activity vs. P. aeruginosa and other Gram -ve bacteria Can cross the blood brain barrier Used to treat meningitis

The Third-generation Cephalosporins include Cefotaxime, ceftazidime, ceftizoxime, and ceftriaxone (all parenteral) as well as Cefdinir, cefditoren, cefpodoxime proxetil, ceftibuten, and cefixime (all oral). Gram-positive bacteria Streptococcus pyogenes, Viridans streptococci, Many Streptococcus pneumoniae, Modest activity against Staphylococcus aureus Gram-negative bacteria Escherichia coli, Klebsiella pneumoniae, Proteus spp. Haemophilus influenzae, Neisseria spp. Some Enterobacteriaceae. Anaerobic bacteria Atypical bacteria Spirochetes Borrelia burgorferi

11. Fourth Generation Cephalosporins Oximinocephalosporins Zwitterionic compounds Enhanced ability to cross the outer membrane of Gram negative bacteria Good affinity for the transpeptidase enzyme Low affinity for some b-lactamases Active vs. Gram +ve cocci and a broad array of Gram -ve bacteria Active vs. P. aeruginosa

Fourth Generation Cephalosporins include cefepime (parenteral). Gram-positive bacteria Streptococcus pyogenes, Viridans streptococci, Many Streptocossus pneumoniae. Modest activity against Staphylococcus aureus Gram-negative bacteria Escherichia coli, Klebsiella pneumoniae, Proteus spp. Haemophilus influenzae, Neisseria spp. Many other Enterobacteriaceae, Pseudomonas aeruginosa. Anaerobic bacteria Atypical bacteria

Newer b-Lactam Antibiotics Thienamycin (Merck 1976)(from Streptomyces cattleya) Potent and wide range of activity vs Gram +ve and Gram -ve bacteria Active vs. Pseudomonas aeruginosa Low toxicity High resistance to b-lactamases Poor stability in solution (ten times less stable than Pen G)

Newer b-Lactam Antibiotics Thienamycin analogues used in the clinic Imipenem Ertapenem(2002) Meropenem

The Carbapenems include Imipenem/cilstatin, Meropenem, and Ertapenem (all parenteral) Gram-positive bacteria Streptococcus pyogenes, Viridans group streptococci, Streptococcus pneumoniae, Modest activity against Staphylococcus aureus, Some enterococci, Listeria monocytogenes Gram-negative bacteria Haemophilus influenzae, Neisseria spp., Enterobacteriaceae, Pseudomonas aeruginosa Anaerobic bacteria Bacteroides fragilis, Most other anaerobes.

Newer b-Lactam Antibiotics Clinically useful monobactam Aztreonam Administered by intravenous injection Can be used for patients with allergies to penicillins and cephalosporins No activity vs. Gram +ve or anaerobic bacteria Active vs. Gram -ve aerobic bacteria

The Monobactams include only Aztreonam, which is parenteral Gram-positive bacteria Gram-negative bacteria Haemophilus influenzae, Neisseria spp. Most Enterobacteriaceae, Many Pseudomonas aeruginosa. Anaerobic bacteria Atypical bacteria

Vancomycin Vancomycin is called a ‘glycopeptide’, meaning that it is a cyclic peptide, with sugar residues attached to it.

Vancomycin Mechanism of Action Bacterial Cell Wall Synthesis (review) http://student.ccbcmd.edu/courses/bio141/lecguide/unit2/control/ppgsynanim.html Penicillin Mechanism of Action (review) http://student.ccbcmd.edu/courses/bio141/lecguide/unit2/control/penres.html Vancomycin Mechanism of Action http://student.ccbcmd.edu/courses/bio141/lecguide/unit2/control/vanres.html

Mechanism of Action of Vancomycin Vancomycin binds to the D-alanyl-D-alanine dipeptide on the peptide side chain of newly synthesized peptidoglycan subunits, preventing them from being incorporated into the cell wall by penicillin-binding proteins (PBPs). In many vancomycin-resistant strains of enterococci, the D-alanyl-D-alanine dipeptide is replaced with D-alanyl-D-lactate, which is not recognized by vancomycin. Thus, the peptidoglycan subunit is appropriately incorporated into the cell wall.

Vancomycin Uses Vancomycin is used to treat aerobic Gram + bacteria, including MRSA and strains of penicillin-resistant Streptococcus pneumoniae Vancomycin is administered intraveneously Vancomycin can also be used to treat anearobic Gram + bacteria, including Clostridium difficile (in the case of a GI infection, Vancomycin can be administered orally). Vancomycin cannot be used to treat Gram – bacteria, since the large size of the vancomycin molecule prohibits its passing of the outer membrane.

Vancomycin Resistance Some Enterococci have developed resistance to vancomycin (Enterococcus faecium and Enterococcus faecalis). These bacteria are called Vancomycin Resistant Enterococci (VRE) The mechanism of resistance involves the transformation of the D-Ala-D-Ala linkage in the peptide side chain into D-Ala-D-Lac (i.e. replacement of the NH2 group by an OH group) This terminal linkage is still recognized by the essential PBP’s (so the cell wall can still be constructed), but is not recognized by vancomycin (thus resulting in resistance).

Antimicrobial Activity of Vancomycin Gram-positive bacteria Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus pyogenes. Viridans group streptococci, Streptococcus pneumoniae, Some enterococci. Gram-negative bacteria Anaerobic bacteria Clostridium spp. Other Gram-positive anaerobes. Atypical bacteria

Daptomycin Daptomycin is called a lipopeptide antibiotic Approved for use in 2003 Lipid portion inserts into the bacterial cytoplasmic membrane where it forms an ion-conducting channel. Marketed under the trade name Cubicin

Uses of Daptomycin Daptomycin is active against many aerobic Gram-positive bacteria Includes activity against MRSA, penicillin-resistant Streptococcus pneumoniae, and some vancomycin-resistant Enterococci (VRE) Daptomycin is not active against Gram negative strains, since it cannot penetrate the outer membrane. Primarily been used to treat skin and soft tissue infections Poor activity in the lung.

Antimicrobial Activity of Daptomycin Gram-positive bacteria Streptococcus pyogenes, Viridans group streptococci, Streptococcus pneumoniae, Staphylococci, Enterococci. Gram-negative bacteria Anaerobic bacteria Some Clostridium spp. Atypical

Rifamycins Rifampin is the oldest and most widely used of the rifamycins Rifampin is also the most potent inducer of the cytochrome P450 system Therefore, Rifabutin is favored over rifampin in individuals who are simultaneously being treated for tuberculosis and HIV infection, since it will not result in oxidation of the antiviral drugs the patient is taking Rifaximin is a poorly absorbed rifamycin that is used for treatment of travelers’ diarrhea.

Mechanism of Action of Rifampin Rifampin inhibits transcription by inactivating bacterial RNA polymerase Resistance develops relatively easily, and can result from one of a number of single mutations in the baqcterial gene that encodes RNA polymerase. Therefore, Rifampin is rarely used as monotherapy (i.e. not used as a single agent) but usually combined with other antibiotics

Uses of Rifampin Used, in combination with other drugs, to treat Mycobacterium tuberculosis Used to treat some Staphylococcal infections.

The Rifamycins include Rifampin, Rifabutin, Rifapentine, and Rifaximin, all of which can be administered orally. Rifampin can also be administered parenterally. Gram-positive bacteria Staphylococci Gram-negative bacteria Haemophilus influenzae, Neisseria meningitidis Anaerobic bacteria Mycobacteria Mycobacterium tuberculosis, Mycobacterium avium complex, Mycobacteriumleprae.

Aminoglycosides The structure of the aminoglycoside amikacin. Features of aminoglycosides include amino sugars bound by glycosidic linkages to a relatively conserved six-membered ring that itself contains amino group substituents.

Aminoglycoside Mechanism of Action Aminoglycosides bind to the 30S subunit of the bacterial ribosome, thereby inhibiting bacterial protein synthesis (translation) http://www.microbelibrary.org/microbelibrary/files/ccImages/Articleimages/kaiser/mechanisms/altribo_antibiot.html

Uses of Aminoglycoside Antibiotics Unlike vancomycin, the aminoglycosides have excellent activity against Gram – aerobic bacteria Their extensive positive charge enables them to bind to and penetrate the negatively charged outer membrane and get into the periplasm They are further transported into the cytoplasm by a bacterial transport system.

Lipopolysaccharide is Part of the Outer Membrane of Gram Negative Bacteria

Bacterial lipopolysaccharides are toxic to animals Bacterial lipopolysaccharides are toxic to animals. When injected in small amounts LPS or endotoxin activates several host responses that lead to fever, inflammation and shock. Endotoxins may play a role in infection by any Gram-negative bacterium. The toxic component of endotoxin (LPS) is Lipid A. The O-specific polysaccharide may provide for adherence or resistance to phagocytosis, in the same manner as fimbriae and capsules. The O polysaccharide (also referred to as the O antigen) also accounts for multiple antigenic types (serotypes) among Gram-negative bacterial pathogens. Thus, E. coli O157 (the Jack-in-the-Box and Stock Pavillion E. coli) is #157 of the different antigenic types of E. coli and may be identified on this basis.

Bacterial resistance to aminoglycosides occurs via one of three mechanisms that prevent the normal binding of the antibiotic to its ribosomal target: Efflux pumps prevent accumulation of the aminoglycoside in the cytosol of the bacterium. Modification of the aminoglycoside prevents binding to the ribosome. Mutations within the ribosome prevent aminoglycoside binding.

The Aminoglycosides include Streptomycin, Gentamicin, Tobramycin, and Amikacin (all parenteral), as well as Neomycin (oral). Gram-positive bacteria Used synergistically against some: Staphylococci, Streptococci, Enterococci, and Listeria monocytogenes Gram-negative bacteria Haemophilus influenzae, Enterobacteiaceae, Pseudomonas aeruginosa Anaerobic bacteria Atypical bacteria Mycobacteria Mycobacterium tuberculosis, Mycobacterium avium complex.

Macrolides and Ketolides The structures of erythromycin and telithromycin Circled substituents and distinguish telithromycin from the macrolides. Substituent allows telithromycin to bind to a second site on the bacterial ribosome.

Mechanism of Action of Macrolide Antibiotics Macrolides bind tightly to the 50S subunit of the bacterial ribosome, thus blocking the exit of the newly synthesized peptide Thus, they are interfering with bacterial translation http://www.microbelibrary.org/microbelibrary/files/ccImages/Articleimages/kaiser/mechanisms/altribo_antibiot.html

Uses of Macrolide Antibiotics Active against a broad range of bacteria Effective against some stphylococci and streptococci, but not usually used for MRSA or penicillin-resistant streptococci Most aerobic Gram- bacteria are resistant Active against many atypical bacteria and some mycobacteria and spirochetes

The macrolide group consists of Erythromycin, Clarithromycin, and Azithromycin (all oral, with erythromycin and azithromycin also being available parenterally). Gram-positive bacteria Some Streptococcus pyogenes. Some viridans streptococci, Some Streptococcus pneumoniae. Some Staphylococcus aureus. Gram-negative bacteria Neiseria spp. Some Haemophilus influenzae. Bordetella pertussis Anaerobic bacteria Atypical bacteria Chlamydia spp. Mycoplasma spp. Legionella pneumophila, Some Rickettsia spp. Mycobacteria Mycobacterium avium complex, Mycobacterium leprae. Spirochetes Treponema pallidum, Borrelia burgdorferi.

Uses of Telithromycin (a ketolide) Telithromycin is approved for use against bacterial respiratory infections Active against most strains of Streptococcus pneumoniae, including penicillin- and macrolide-resistant strains Also active against more strains of Staphylococci Only available in oral formulation

The related ketolide class consists of Telithromycin (oral). Gram-positive bacteria Streptococcus pyogenes, Streptococcus pneumoniae, Some Staphylococcus aureus Gram-negative bacteria Some Haemophilus influenzae, Bordetella pertussis Anaerobic bacteria Atypical bacteria Chlamydia spp. Mycoplasma spp. Legionella pneumophila

The Tetracycline Antibiotics The structure of tetracycline

Tetracycline Antibiotics Tigecycline Doxycycline

Mechanism of Action of the Tetracycline Antibiotics The tetracyclines bind to the 30S subunit of the bacterial ribosome and prevent binding by tRNA molecules loaded with amino acids. http://student.ccbcmd.edu/courses/bio141/lecguide/unit2/control/tetres.html

Uses of the Tetracycline Antibiotics Main use is against atypical bacteria, including reckettsiae, chlamydiae, and mycoplasmas Also active agains some aerobic Gram-positive pathogens and some aerobic Gram-negative bacteria

The Tetracycline Class of Antibiotics consists of Doxycycline and Tigecycline (parenteral) as well as Tetracycline, Doxycycline and Minocycline (oral) Gram-positive bacteria Some Streptococcus pneumoniae Gram-negative bacteria Haemophilus influenzae, Neisseria meningitidis Anaerobic bacteria Some Clostridia spp. Borrelia burgdorferi, Treponema pallidum Atypical bacteria Rickettsia spp. Chlamydia spp.

Tigecycline

The antimicrobial activity of Tigecycline (parenteral) Gram-positive bacteria Streptococcus pyogenes. Viridans group streptococci, Streptococcus pneumoniae, Staphylococci, Enterococci, Listeria monocytogenes Gram-negative bacteria Haemophilus influenzae, Neisseria spp. Enterobacteriaceae Anaerobic bacteria Bacteroides fragilis, Many other anaerobes Atypical bacteria Mycoplasma spp.

Chloramphenicol

Mechanism of Action of Chloroamphenicol Binds to the 50S subunit of the bacterial ribosome, where it blocks binding of tRNA

Uses of Chloramphenicol Severe toxicity limits utility The most serious side effect of chloramphenicol treatment is aplastic anaemia (a condition where bone marrow does not produce sufficient new cells to replenish blood cells) This effect is rare and is generally fatal: there is no treatment and there is no way of predicting who may or may not get this side effect. The effect usually occurs weeks or months after chloramphenicol treatment has been stopped.

Uses of Chloramphenicol However, despite its toxicity, chloramphenicol has a wide spectrum of activity, that includes many aerobic Gram-positive, Gram-negative, anaerobic, and atypical bacteria

The Antimicrobial Activity of Chloramphenicol Gram-positive bacteria Streptococcus pyogenes, Viridans group streptococci. Some Streptococcus pneumoniae Gram-negative bacteria Haemophilus influenzae, Neisseria spp. Salmonella spp. Shigella spp. Anaerobic bacteria Bacteroides fragilis. Some Clostridia spp. Other anaerobic Gram-positive and Gram negative bacteria Atypical bacteria Rickettsia spp. Chlamydia trachomatis, Mycoplasma spp.

Clindamycin

Mechanism of Action of Clindamycin Clindamycin binds to the 50S subunit of the ribosome to inhibit protein synthesis

Uses of Clindamycin Clindamycin is a member of the lincosamide series of antibiotics Main utility is in treatment of Gram-positive bacteria and anaerobic bacteria Active against staphylococcus, including some strains of MRSA Not useful against Gram-negative bacteria

Toxicity of Clindamycin Clindamycin kills many components of the gastrointestinalo flora, leaving only Clostridium difficile This can result in overgrowth by C. difficile, which is resistant

The Antimicrobial Activity of Clindamycin (both oral and parenteral) Gram-positive bacteria Some Streptococcus pyogenes, Some viridans group streptococci. Some Streptococcus pneumoniae, Some Staphylococcus aureus Gram-negative bacteria Anaerobic bacteria Some Bacteroides fragilis, Some Clostridium spp. Most other anaerobes. Atypical bacteria

Streptogramins

Mechanism of Action of Streptogramins Dalfopristin inhibits the early phase of protein synthesis in the bacterial ribosome and quinupristin inhibits the late phase of protein synthesis. The combination of the two components acts synergistically and is more effective in vitro than each component alone.

Uses of the Streptogramins Have activity against Gram positive aerobic bacteria Including MRSA, penicillin-resistant Streptococcus pneumoniae and some VRE (active against vancomycin resistant Enterococcus faecelis, but not Enterococcus faecium) The Quinupristin/Dalfopristin mixture is marketed as Synercid

The Antimicrobial Activity of Quinupristin/Dalfopristin (parenteral) Gram-positive bacteria Streptococcus pyogenes, Viridans group streptococci, Streptococcus pneumoniae, Staphylococcus aureus, Some enterococci. Gram-negative bacteria Anaerobic bacteria Atypical bacteria

The structure of Linezolide The Oxazolidinones The structure of Linezolide

Mechanism of Action of the Oxazolidinones Binds to the 50S subunit and prevents association of this unit with the 30S subunit. http://student.ccbcmd.edu/courses/bio141/lecguide/unit6/genetics/protsyn/translation/oxazolres_anim.html

Uses of the Oxazolidinones Has excellent activity against most aerobic Gram-positive bacteria, including MRSA and VRE. Only oxazolidonone on the market now is Linezolid, which is both oral and intravenous.

The Antimicrobial Activity of Linezolid (both oral and parenteral) Gram-positive bacteria Streptococcus pyogenes. Viridans group streptococci, Streptococcus pneumoniae, Staphylococci, Enterococci. Gram-negative bacteria Anaerobic bacteria Atypical bacteria

The Sulfa Drugs Most commonly used sulfa drug is a mixture of the sulfa drug Sulfamethoxazole and Trimethoprim These two drugs work in synergy, with the combination being superior to either drug alone. This combination is known as co-trimoxazole, TMP-sulfa, or TMP-SMX Sulfamethoxazole Trimethoprim

Mechanism of Activity of Sulfa Drugs Trimethoprim-sulfamethoxazole works by preventing the synthesis of tetrahydrofolate (THF), an essential cofactor for the metabolic pathways that generate deoxynucleotides, the building blocks of DNA.

Tetrahydrofolic Acid Biosynthetic Pathway In the first step of the pathway, the sulfonamides are mistaken for the natural substrate, p-aminobenzoic acid (PABA) and the drug acts as a competitive inhibitor of this enzyme In a later step, the trimethoprim acts as a structural analog of dihydrofolate and therefore inhibits dihydrofolate reductase

Structural Resemblance of Sulfamethoxazole and p-Aminobenzoic Acid

Another sulfa drug is Dapsone, which is used to treat Mycobacterium leprae

Structural Comparison of Two Sulfa Drugs

The Antimicrobial Activity of the Sulfa Drugs Gram-positive bacteria Some Sreptococcus pneumoniae, Some Staphylococci, Listeria monocytogenes Gram-negative bacteria Some Haemophilus influenzae, Some Enterobacteriaceae Anaerobic bacteria Atypical bacteria Mycobacteria (Dapsone) Mycobacterium leprae

The Fluoroquinolones

Mechanism of Action: Quinolones Quinolone antibiotics inhibit bacterial DNA gyrase (Gram negative bacteria) or Topoisomerase IV (Gram positive bacteria) http://can-r.ca/images/Flash/fluoroquinolones.swf

Uses of the Quinolone Antibiotics Urinary Tract Infections: fluoroquinolones are more effective than trimethoprim-sulfamethoxazole Prostatitis Respiratory tract infections Gastrointestinal and Abdominal Infections

Antimicrobial Activity of the Quinolones (oral) Gram-positive bacteria Some Staphylococcus aureus, Streptococcus pyogenes, Virdans group streptococci, Streptococcus pneumoniae Gram-negative bacteria Neisseria spp. Haemophilus influenzae Many Enterobacteriaceae, Some Pseudomonas aeruginosa Anaerobic bacteria Some clostridia spp, Some Bacteroides spp. Atypical bacteria Chlamydia and Chlamydophilia, Mycoplasma pneumoniae, Legionella spp Mycobacteria Mycobacterium tuberculosis, Mycobacterium avium complex, Mycobacterium leprae

Metronidazole (Flagyl) Metronidazole is used in the treatment of infections caused by anaerobic bacteria

Metronidazole Mechanism of Action Metronidazole is a prodrug. It is converted in anaerobic organisms by the redox enzyme pyruvate-ferredoxin oxidoreductase. The nitro group of metronidazole is chemically reduced by ferredoxin (or a ferredoxin-linked metabolic process) and the products are responsible for disrupting the DNA helical structure, thus inhibiting nucleic acid synthesis.

Mechanism of Action of Metronidazole Metronidazole is selectively taken up by anaerobic bacteria and sensitive protozoal organisms because of the ability of these organisms to reduce metronidazole to its active form intracellularly.

Systemic metronidazole is indicated for the treatment of: Vaginitis due to Trichomonas vaginalis (protozoal) infection in both symptomatic patients as well as their asymptomatic sexual contacts; Pelvic inflammatory disease in conjunction with other antibiotics such as ofloxacin, levofloxacin, or ceftriaxone Protozoal infections due to Entamoeba histolytica (Amoebic dysentery or Hepatic abscesses), and Giardia lamblia (Giardiasis) should be treated alone or in conjunction with iodoquinol or diloxanide furoate Anaerobic bacterial infections such as Bacteroides fragilis, spp, Fusobacterium spp, Clostridium spp, Peptostreptococcus spp, Prevotella spp, or any other anaerobes in intraabdominal abscess, peritonitis, empyema, pneumonia, aspiration pneumonia, lung abscess, diabetic foot ulcer, meningitis and brain abscess, bone and joint infections, septicemia, endometritis, tubo-ovarian abscess, or endocarditis Pseudomembranous colitis due to Clostridium difficile Helicobacter pylori eradication therapy, as part of a multi-drug regimen in peptic ulcer disease Prophylaxis for those undergoing potentially contaminated colorectal surgery and may be combined with neomycin

Antimicrobial Activity of Metronidazole (both oral and intravenous) Gram-positive bacteria Gram-negative bacteria Anaerobic bacteria Bacteroides fragilis, Clostridium spp. Most other anaerobes Atypical bacteria

Antimicobacterial Agents Mycobacterial infections are very slow progressing Many antibiotics have poor activity against slow growing infections Mycobacteria must be treated for a long time, and therefore, may readily develop resistance to a single antibiotic Typically, several antibiotic agents are used simultaneously

Antimycobacterial Agents Pyrazinamide Rifampin Ethambutol

Mycobacterial Infections http://www.nature.com/nrmicro/animation/imp_animation/index.html http://web.uct.ac.za/depts/mmi/lsteyn/cellwall.html

Mycolic Acids provide protection Mycolic acids are long fatty acids found in the cell walls of the mycolata taxon, a group of bacteria that includes Mycobacterium tuberculosis, the causative agent of the disease tuberculosis. They form the major component of the cell wall of mycolata species. The presence of mycolic acids gives M. tuberculosis many characteristics that defy medical treatment. They lend the organism increased resistance to chemical damage and dehydration, and prevent the effective activity of hydrophobic antibiotics. In addition, the mycolic acids allow the bacterium to grow readily inside macrophages, effectively hiding it from the host's immune system.

Mechanism of Action of Anti-Mycobacterial Antibiotics Rifampin is an inhibitor of RNA polymerase Isoniazide inhibits the synthesis of mycolic acid Pyrazinoic acid inhibits the enzyme fatty acid synthetase I, which is required by the bacterium to synthesise fatty acids. Ethambutol disrupts the formation of the cell wall